Presse Med.

2016; 45: e111–e117

on line on
www.em-consulte.com/revue/lpm
SEPTIC SHOCK
www.sciencedirect.com

Quarterly Medical Review

Antimicrobial therapy in patients with septic

shock

Bruno Pastene, Gary Duclos, Claude Martin, Marc Leone

Available online: 6 April 2016 Aix Marseille université, Assistance publique–Hôpitaux de Marseille, hôpital Nord,
service d'anesthésie et de réanimation, 13015 Marseille, France

Correspondence:
Marc Leone, Aix Marseille université, Assistance publique–Hôpitaux de Marseille,
hôpital Nord, service d'anesthésie et de réanimation, 13015 Marseille, France.
marc.leone@ap-hm.fr

Summary
In this issue
Septic shock: a global
Providing antibiotics is a life-saving intervention in patients with septic shock. Cultures as clinically
response appropriate before antimicrobial therapy are required. Guidelines recommend providing broad-
M. Leone, France spectrum antibiotics within the first hour after recognition of shock. The site of infection, the
Pathophysiology of septic patient's history and clinical status, and the local ecology all affect the choice of empirical
shock: from bench to treatment. The appropriateness of this choice is an important determinant of patient outcome.
bedside
K.W. McConnell, At 48-96 h, the antimicrobial treatment should be systematically reassessed based on the clinical
C. Coopersmith, United course and culture results. Cessation, de-escalation, continuation, or escalation are discussed
States according to these variables. Unnecessary treatment should be avoided to reduce the emergence
Current haemodynamic of multidrug resistant pathogens.
management of septic
shock
J.-L. Vincent, D. Obergozo
Ortes, A. Acheampong,
Belgium
Adjunctive treatment in Introduction
septic shock: what's next? In intensive care units (ICU), more than 75% of patients receive at least one antibiotic during their
D. Annane, France
stay in the hospital. The rationale for giving antibiotics is that patients with a microbiologically
Antimicrobial therapy in
confirmed infection have a greater mortality rate than those without infection [1]. At first glance,
patients with septic shock
B. Pastene, G. Duclos, the prompt initiation of appropriate antimicrobial therapy saves lives and ICU resources [2–4].
C. Martin, M. Leone, France However, wide use of broad-spectrum antibiotics leads to the emergence of resistance (figure 1).
The growing prevalence of these pathogens in recent years has become a significant public health
threat because they are associated with an increased rate of inappropriate empirical antimicrobial
therapy [5]. Thus, development of strategies to reduce antibiotic consumption in ICU patients is
becoming crucial.

Method
This article is based on a PubMed search using "sepsis'', "empirical'', "antibiotics'', "de-escalation''
and "ICU'' as keywords. The search focused on the 2010-2015 period but previous references were
added when the authors considered it appropriate, especially for seminal articles. We selected
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http://dx.doi.org/10.1016/j.lpm.2016.03.006
© 2016 Elsevier Masson SAS. All rights reserved.
 B. Pastene, G. Duclos, C. Martin, M. Leone
Broad spectrum
antibiotics
Death MDR
Inappropriate
Antibiotic Therapy
Figure 1
Vicious circle of overuse of antibiotics (MDR: multidrug resistant
bacteria)
references related to ICU patients. Whenever possible, guide-
lines from professional societies were cited.
Definitions
Empirical antimicrobial therapy refers to the initiation of treat-
ment before the determination of a firm diagnosis. Generally,
this term is used to describe treatment for patients receiving
antibiotics before identification of the specific microorganism
causing the infection. Inappropriate empirical antimicrobial
therapy is defined by the absence of an antimicrobial agent
directed against the specific class of microorganisms responsible
for the infection and the administration of an antimicrobial
agent to which the microorganism responsible for infection is
resistant. "Broad spectrum antibiotics'' refers to antibiotics
with activity against Pseudomonas aeruginosa while "broad
spectrum antimicrobial therapy'' refers to the combination of
antibiotics with activity against P. aeruginosa and methicillin-
resistant Staphylococcus aureus (MRSA). A joint task force from
the European centre for disease prevention and control and the
United States centers for disease control and prevention has
defined resistant organisms as follows: a multidrug-resistant
organism (MDR) is one with acquired non-susceptibility to at
least one agent in three or more antimicrobial categories; an
extensively drug-resistant organism (XDR) to at least one
agent in all but two or fewer antimicrobial categories, and a
pandrug-resistant organism (PDR) to all agents in all antimicro-
bial categories [6].
Empirical antimicrobial therapy
Principles
Empirical antimicrobial therapy is used if a suspected severe
infection is likely to impair patient outcome. The driving force
behind this strategy is the consistent finding that delays in the
initiation of appropriate antibiotic therapy in patients with
severe infection is associated with increased mortality [2–4].
Patients suspected of having an infection and hemodynamic
e112
impairment are candidates for empirical antimicrobial therapy.
Such treatment is also required in selected infections such as
severe sepsis, meningitis, pneumonia, peritonitis, pyelonephri-
tis, and endocarditis, and in specific patient populations (e.g.,
with neutropenia or splenectomy). Waiting for results of micro-
biological culture before introducing antibiotics in those specific
groups of patients cannot be recommended.
The challenge in the selection of initial empirical therapy is
to provide an appropriate therapy without microbiological
documentation, given that inappropriate antibiotic therapy is
associated with increased mortality in critically ill patients [5].
Adherence to guidelines seems to be associated with an
increased rate of appropriate therapy [7,8].
In order to minimize the risk of failure, broad-spectrum anti-
biotics are typically used. However, this approach results in
greater use of antibiotics than decisions based on culture find-
ings [9] and may be associated with the emergence of MDR,
Clostridium difficile infections, and increased costs. Empirical
antibiotic therapy must always be re-assessed at 48-96 h and
tailored as soon as cultures and sensitivity profiles become
available.
Best timing for providing an empirical antimicrobial
therapy
For each patient, antimicrobial therapy may be initiated on an
emergency, urgent, or delayed basis. Emergency is defined by
the need to start antibiotics within 1 h after diagnosis, urgent by
the start of antibiotics within 6-8 h after diagnosis, and delayed
by the start of antibiotics within 8-24 h after diagnosis. It is
critical to underline that the benefit for administering antibiotics
within 1 h after shock recognition was not confirmed in a recent
systematic review of literature [10].
Whatever the timing of antibiotic initiation, samples including
blood cultures are required before the first administration. In
a large observational study, obtaining blood cultures before
antibiotics were administered was associated with improved
survival [11]. Although this result probably reflects good prac-
tices, obtaining blood cultures may also serve to refine the
treatment after bacteriological results are obtained.
Emergency empirical antimicrobial therapy is required in
patients with hemodynamic impairment and suspected infec-
tion. Severe sepsis is defined by the association of signs of sepsis
and organ dysfunction (cardiovascular, pulmonary, neurologic,
and hepatic). Septic shock is defined by the need to introduce
vasopressors in a patient with a suspected infection. Several
studies of patients with severe sepsis and septic shock have
shown that the administration of antibiotics within the
first hours after diagnosis is associated with improved survival
[2–4,11] despite the findings of the systematic literature review
described above [10]. Each hour of delay in antibiotic adminis-
tration after diagnosis has been associated with an average
decrease in survival of 7.6%; every 10-min delay decreases
tome 45 > n84P2 > April 2016
Antimicrobial therapy in patients with septic shock
survival by 1% [4]. Thus, guidelines recommend the prompt
introduction of antimicrobial therapy in these patients [12].
Bacterial meningitis is another indication for emergency anti-
microbial therapy [13]. In a seminal study, an interval between
admission and antibiotic therapy longer than 3 h was the stron-
gest predictor of mortality [14]. Sepsis in splenectomized or
neutropenic patients should also be treated without delay. After
splenectomy, pneumococci account for 50–90% of infections
and may be associated with mortality of up to 60% [15].
The most common situation encountered in patients with infec-
tion probably involves the need for urgent antibiotic therapy.
Progressive change in the clinical picture over several hours
indicate the need to initiate antibiotic therapy, as seen
frequently in mechanically ventilated patients with fever, whose
chest radiography images worsen over the course of a day.
Sometimes, other investigations, such as a computed tomogra-
phy scan or ultrasound may serve to confirm the diagnosis. Gram
stain results may facilitate the decision, in view of their excellent
negative predictive value [16].
For community-acquired pneumonia, the American Thoracic
Society/Infectious Diseases Society of America (ATS/IDSA)
guidelines recommend that the first antibiotic dose be given
in the emergency department [17]. Empirical antibiotics
should be initiated in patients with suspected hospital-
acquired pneumonia in the presence of a new or progressive
radiographic infiltrate plus at least two of three clinical fea-
tures (fever > 38 8C, leukocytosis or leukopenia, and purulent
secretions) [18].
Antimicrobial therapy for intra-abdominal infection should be
initiated without delay [19]. A common error is to administer
antibiotics after the source control in order to collect samples
before antimicrobials are administered.
Criteria of choice
A judicious choice of antimicrobial therapy should be based on
the host characteristics, site of infection, local ecology, and
the pharmacokinetics/pharmacodynamics of the antibiotics.
Toxicity and costs should also be considered. As guidelines
have specifically described the use of antibiotics in each
condition, hereafter, we report only the principles of antibiotic
choice.
Host characteristics
Standard risk factors for MDR carriage are antibiotic treatment in
the preceding 90 days, a current hospitalization of 5 days or
more, a high frequency of antibiotic resistance in either the
community or the specific hospital unit, hospitalization of 2 days
or more in the preceding 90 days, residence in a nursing home
or extended care facility, home infusion therapy, home wound
care, a family member with MDR, and immunosuppression [18].
Suspicion is warranted for travellers coming from – and
especially hospitalized in – countries with high incidence of
MDR [20].
tome 45 > n84P2 > April 2016
SEPTIC SHOCK
Site of infection
The site of infection is one of the major determinants in the
choice of antibiotics. The respiratory tract (63%), abdomen
(20%), bloodstream (15%), and urinary tract (14%) are the
most frequent sites reported for ICU infections [1]. For patients
without risk factors for MDR carriage, ventilator-associated
pneumonia is generally related to Streptococcus pneumoniae,
Haemophilus influenzae, S. aureus, Legionella spp., Myco-
plasma pneumoniae, Chlamydia pneumoniae, and viruses
[18]. For patients with risk factors for MDR pathogen carriage,
P. aeruginosa, Acinetobacter baumannii, Klebsiella pneumo-
niae and MRSA should be suspected [18].
Intra-abdominal infections are generally polymicrobial with
Gram-negative bacteria (E. coli, Enterobacter spp. and Klebsiella
spp.), Gram-positive bacteria (enterococci in 20% of the cases)
and anaerobes (Bacteroides sp. in 80% of the cases). For
patients with identified risk factors, or those with tertiary
intra-abdominal infection, MDR (including P. aeruginosa, A.
baumannii and MRSA) and yeasts should be suspected [19].
Skin infections are frequently polymicrobial. Suspected bacteria
should be Streptococcus spp. (40%), S. aureus (30%), anae-
robes (30%), and Gram-negative bacteria (10–20%). Bacterial
cerebrospinal fluid infections in outpatients are due to S. pneu-
moniae (35%) and Neisseria meningitidis (32%) [14].
Local ecology
Knowledge of local bacteriologic patterns increases the likeli-
hood of prescribing appropriate antimicrobial therapy. Regular
surveillance cultures for guiding empirical therapy are sug-
gested to assess the level of resistance in specific units [21].
Regular culture surveillance is critical for revising local proto-
cols according to local ecology changes. A meta-analysis has
shown that surveillance cultures facilitate prediction of MDR
[22]. However, they are also time-consuming and costly.
Routinely, clinical screening of patients at ICU admission
may predict the risk of MDR colonization and thereby avoid
the need for systematic surveillance cultures [23]. In addition,
the real impact of such systematic cultures on the choice of
empirical antibiotics remains uncertain. In contrast, a regular
assessment of the local ecology within the ICU is probably
important to optimize the success of an empiric antimicrobial
therapy [24].
Pharmacokinetics/pharmacodynamics
ICU patients develop pathophysiological changes during their
hospitalization that affects the antibiotic pharmacokinetics and
thus necessitates adaptation of doses and intervals [25,26].
Volume of distribution and clearance are generally altered.
An increase in volume of distribution typically affects hydrophilic
antibiotics and may warrant an increase in the initial dosing
requirements to achieve the target drug concentrations [26].
Clearance changes affect day-to-day dosing requirements for
patients developing very high clearance due to increases in
e113
 B. Pastene, G. Duclos, C. Martin, M. Leone
capillary permeability and the development of "third-spacing''
[27]. The disproportionate redistribution of albumin from intra-
vascular to extravascular compartments results in low plasma
albumin concentrations and profoundly affects the pharmacoki-
netics of antibiotics that bind to serum albumin [28].
Pharmacokinetic/pharmacodynamic optimization of antibiotics
is a critical tool for improving dosing regimens for ICU patients
[26–28]. The bedside variability of patients with sepsis is
extreme. Therapeutic drug monitoring is probably the best
option for optimizing antibiotic dosage, although strong evi-
dence for this is scarce [29,30]. In a recent survey, therapeutic
drug monitoring of vancomycin, piperacillin/tazobactam, and
meropenem was used by 74%, 1% and 2% of the respondents,
respectively [31].
For aminoglycosides, which are concentration-dependent, the
recommended approach is the use of high once-a-day doses in
order to achieve an adequate peak serum concentration. It is
strongly recommended to limit prescriptions to 3 days maxi-
mum [24]. For beta-lactams, a time-dependent class of anti-
biotics, the administration of a loading dose followed by a
continuous infusion seems the best way to achieve effective-
ness [32]. A large randomized clinical trial failed to show a
survival benefit with this strategy [33], but a higher rate of
clinical cure has been obtained elsewhere [34]. Glycopeptides
are also time-dependent. Administration of high doses by con-
tinuous infusion is recommended, based on monitoring of
plasma concentrations [24].
Monotherapy versus combination therapy
Combined antibiotic therapy is widely used in clinical practice and
is aimed at widening the spectrum of activity of antimicrobial
therapy, increasing bactericidal activity, and preventing the devel-
opment of resistance. Combination is recommended for patients
with septic shock [12]. The impact of combination therapy for
infections with Gram-negative bacteria has been evaluated by
several studies and summarized in a meta-analysis [35]. The
clinical data supporting the superiority of combination therapy
versus monotherapy are neither overwhelming nor definitive. The
greatest benefit of combination antibiotic therapy is to increase
the likelihood of using an effective agent during empiric therapy,
rather than exploitation of in vitro synergy or the prevention of
resistance during definitive treatment. In contrast, increased tox-
icity with combination therapy has been well-documented. Due
to the increased mortality rate associated with delays in appro-
priate, effective antimicrobial treatment, initiating broad-spec-
trum empirical antimicrobial treatment (which often means
combination therapy) at the onset of septic shock seems prudent.
A combination of beta-lactam and aminoglycoside should be
preferred to that of beta-lactam and fluoroquinolones, even in
patients with renal impairment [24,36].
Specific infections may require combination therapy, including,
for example, infections in patients with risk factors for MDR. A
e114
combination therapy for infections due to carbapenemase-
producing K. pneumoniae strains seems superior to monother-
apy in terms of mortality [37]. Neutropenic patients also require
a combination of antibiotics.
Reassessment of antimicrobial treatment
after culture results
De-escalation strategy
Reducing the spectrum and number of antibiotics as soon as
the responsible pathogen is identified is, theoretically, an
effective method to decrease the exposure of patients to
antibiotics [38]. The definition of de-escalation remains mat-
ter of debate, although a French study group reached a
consensus for a basic definition [39]. An earlier French ran-
domized clinical trial applied a definition making the following
changes once the susceptibility and culture results for the
suspected causative bacteria were available: switch the
"pivotal'' antibiotic for empirical treatment to an antibiotic
with a spectrum as narrow as possible; stop the companion
drug (aminoglycoside or fluoroquinolone or macrolide) on
day 3; and stop the empirical antibiotics against MRSA if MRSA
was not identified in "microbiological cultures'' [40].
This strategy has not negatively impacted outcomes in three
observational studies [41–43], although it should be noted
that empirical treatment was preferentially de-escalated in
patients with an early positive clinical response [43]. Two
randomized clinical trials did not confirm these findings
[40,44]. In one, de-escalation of antibiotic treatment resulted
in prolonging the ICU stay, but the mortality rate was unaf-
fected [40]. Current evidence suggests that de-escalation
should depend on the relevance of cultures and clinical course
(figure 2). The presumed "positive'' impact of de-escalation
on local microbial ecology remains to be confirmed in well-
conducted studies [38].
Figure 2
Strategy for the decision of de-escalation according to clinical
severity and sample quality
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Antimicrobial therapy in patients with septic shock
SEPTIC SHOCK

Shortening the duration of antimicrobial therapy TABLE I

Excessive treatment duration is probably a major cause of the Reduction of antibiotic exposure
emergence of MDR pathogens. For ventilator-acquired pneumo-
nia, in the absence of a non-fermenting Gram-negative bacilli Interventions to reduce antibiotic exposure
infection, a fixed 7- or 8-day course of antibiotic therapy seems Restrict antibiotic treatment for documented infections unless life-
adequate [45]. In the presence of such bacilli, a prolonged 12- to threatening conditions
15-day course has been associated with a lower rate of recur-
Optimize pharmacokinetics/pharmacodynamics
rence than the 8-day course [45]. For bloodstream infections,
no significant difference in cure or survival was detected for Use combination therapy only in patients with shock
bacteremic patients receiving shorter (5-7 days) versus longer Reassess continuously the need for antibiotics
(7-21) therapy [46]. The French guidelines on intra-abdominal
Shorten duration of antibiotic treatment
infections recommend a duration of 5 to 15 days for postoper-
ative and healthcare-associated infections [19]. Future studies Identify a referent infectious disease specialist in the intensive care
unit
should confirm if short durations are safe in those patients. Short
durations have also been suggested for urinary tract infections Adhere to your local protocols
[47].
Procalcitonin-guided antibiotic discontinuation is a growing field
of research. The monitoring of procalcitonin level as a guide to
cessation of an antibiotic therapy has been associated with a
diminution of antibiotic duration with no effect on mortality [48].
Adherence to this concept should lead to stopping treatment in
patients with low procalcitonin levels or significant decreases
between two measurements. However, there is a need for evi-
dence supporting this strategy in units with protocols of short-
duration antimicrobial therapy. Finally, in patients with negative
cultures, antibiotics can probably be stopped safely [49]. Inves-
tigations are required to understand the cause of shock.
Specificities of MRSA infections
Vancomycin should be used as first-line therapy in patients with
MRSA infection. Administration using bolus and continuous Figure 3
infusion is recommended. The goal is to reach high plasma Decision about antimicrobial treatment: interactions between
concentration (> 20 mg/L). Other antibiotics should be dis- health professionals
cussed based on the assessment of both renal function and
the minimal inhibitory concentration. Linezolid is recommended
for ventilator-associated pneumonia due to MRSA when the dynamic strategy [52]. These protocols should include the entire
minimal inhibitory concentration for vancomycin is greater than process aiming at reducing antibiotic exposure (table I).
1 mg/L or renal impairment is present. Daptomycin seems to be
an interesting option for treating patients with bacteremia or Conclusion
endocarditis due to MRSA in the same circumstances [24]. The choice of antibiotics is probably the first determinant of
Formal protocol based on local ecology survival in patients with septic shock. An integrative strategy of
Antimicrobial guidelines, automated antimicrobial utilization dynamic management of antimicrobial treatment for septic
guidelines, and protocols are useful tools for ensuring appropri- patients should be supported by written protocols (figure 3).
ate antibiotic prescription, which in turn reduces the develop- This strategy includes knowledge of local ecology and of the
ment of MDR [7,50]. Inappropriate treatment of infections is patient's history and clinical status. Early reassessment is man-
often secondary to absence or violation of protocols [7]. A datory, based on both the patient's course and the identification
formalized antibiotic discontinuation policy has reduced the of the pathogen in cultures. Short treatment durations should be
duration of antibiotics and thus may positively affect the antibi- the rule for all patients. Efforts are required to avoid excessive
otic resistance profile [51]. Hence, policies aiming at limiting antimicrobial utilization for non-life-threatening infections.
antibiotic prescription should be encouraged to reduce the
Disclosure of interest: M.L. received fees for consulting (Basilea) and
development of antimicrobial resistance [24]. New technology educative support (MSD).
for rapid identification of pathogens should be included in the B.P., G.D. and C.M. declare that they have no competing interest.
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 B. Pastene, G. Duclos, C. Martin, M. Leone
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