Review

Antibiotics and the burn patient

Francois Ravat
a,
*, Ronan Le-Floch
b
, Christophe Vinsonneau
c
, Pierre Ainaud
d
,
Marc Bertin-Maghit
e
, Herve Carsin
f
, Ge rard Perro
g
the Socie te Francaise dEtude et de Traitement des Bru lures (SFETB)
a
Centre des bru le s, Centre hospitalier St Joseph et St Luc, 20 quai Claude Bernard, 69007 Lyon, France
b
Centre des bru le s, Centre hospitalo-universitaire, Nantes, France
c
Centre des bru le s, Groupe hospitalier Cochin, Paris, France
d
Centre des bru le s, Ho pital de la Conception, Marseille, France
e
Centre des bru le s, Ho pital Edouard Herriot, Lyon, France
f
Centre des bru le s, Ho pital dInstruction des Arme es Percy, Clamart, France
g
Centre des bru le s, Ho pital Pellegrin-Tripode, Bordeaux, France
Contents
1. General considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.2. Infection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.3. Dealing with local infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.4. Role of bacterial population (inoculum) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2. Time for onset of antibiotic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3. Bactericidal or bacteriostatic molecules? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4. Association or monotherapy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
5. Adaptation of antibiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
b ur ns 3 7 ( 2 0 1 1 ) 1 6 2 6
a r t i c l e i n f o
Article history:
Accepted 13 October 2009
Keywords:
Antibiotics
Antibiotic therapy
Burn
Burn patient
Bacterial resistance
Pharmacokinetics
Pharmacodynamics
Dosage
a b s t r a c t
Infection is a major problem in burn care and especially when it is due to bacteria with
hospital-acquired multi-resistance to antibiotics. Moreover, when these bacteria are Gram-
negative organisms, the most effective molecules are 20 years old and there is little hope of
any new product available even in the distant future. Therefore, it is obvious that currently
available antibiotics should not be misused. Withthis aiminmind, the following reviewwas
conducted by a group of experts from the French Society for Burn Injuries (SFETB). It
examined key points addressing the management of antibiotics for burn patients: when
to use or not, time of onset, bactericidia, combination, adaptation, de-escalation, treatment
duration and regimen based on pharmacokinetic and pharmacodynamic characteristics of
these compounds. The authors also considered antibioprophylaxis and some other key
points such as: infection diagnosis criteria, bacterial inoculae and local treatment. French
guidelines for the use of antibiotics in burn patients have been designed up from this work.
# 2009 Elsevier Ltd and ISBI. All rights reserved.
* Corresponding author. Tel.: +33 478 61 89 25; fax: +33 478 61 88 77.
E-mail address: fravat@ch-stjoseph-stluc-lyon.fr (F. Ravat).
avai l abl e at www. sci encedi r ect . com
journal homepage: www.elsevier.com/locate/burns
0305-4179/$36.00 # 2009 Elsevier Ltd and ISBI. All rights reserved.
doi:10.1016/j.burns.2009.10.006
6. Duration of antibiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
7. Administration methods (dosage and rhythm of injection) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
7.1. Notions of pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
7.2. Notions of pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
7.3. Regimen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
8. Monitoring antibiotic concentrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
9. Perioperative antibiotic prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
10. Guidelines from the French Society for Burn Injuries (SFETB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
10.1. Guidelines for antibiotic therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
10.2. Guidelines for antibiotics prophylaxis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
10.3. Practical use. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
A study conducted in the French burns centres during the
summer 2006 pointed out that 19% of inpatients developed
an infection. Although these facts are comparable to those
observed in intensive care units, infection is a major problem
in burn care and especially when it is due to bacteria
with hospital-acquired multi-resistance to antibiotics,
which has been proved to be directly related to the
consumption of antibiotics. Moreover, when these bacteria
are Gram-negative organisms, the most effective molecules
are 20 years old and there is no hope to see any newmolecule
available even in the far future. Therefore, it is obvious that
current antibiotics still active should not be overused or
misused.
Thus, the French Society for Burn Injuries (SFETB) has
published guidelines for the use of antibiotics in the burn
patient. These guidelines were drawn up by a group of
experts from the SFETB. Analysis of the literature, synthesis
of the relevant items and drafting the guidelines were led by
three members of the group. The changes, denitive draft
and validation were approved collectively by all the experts,
according to the levels of evidence-based medicine [1,2]. The
following text is the review of literature conducted by
the French group of experts prior to the elaboration of
guidelines.
1. General considerations
1.1. Introduction
Antibiotics should be used by keeping mind that they target
not the patient but the bacteria: the clinician should select
the molecule or molecules with the greatest antibacterial
efcacy and attempt to supply a concentration at the
infection site high enough to kill targeted pathogens
(bactericidia).
Antibiotics should not allow bacterial resistance to arise by
lowering the selection pressure and thereby limiting the
consequences of antibiotics use in terms of bacterial
ecology. Controlling the prescription of antibiotics, espe-
cially by avoiding useless antibiotic therapy, is an excellent
means to decrease emergence of bacterial resistance [35].
Antibiotics are only one of the means to ght infection.
Antibiotic therapy is part of global hospital strategy as well
as hygiene, and others.
1.2. Infection criteria
Diagnosis of infection in burn patient is not easy because
clinical (hyperthermia) and biological (hyperleukocytosis,
increased CRP levels, etc.) infection criteria are poorly
relevant, especially in heavier-burn patients. Actually, a
serious burn triggers a systemic inammatory response
syndrome (SIRS), which mimics usual clinical and biological
signs of infection [69]. Therefore, deciding an antibiotic
therapy based on such usual infection criteria may lead to the
prescription of useless antibiotics. This has led experts to
dene the criteria of infection in burn patient. The retained
criteria are based onthose validatedfor intensive care patients
withtwo particular characteristics, namely the general criteria
of infection and criteria for burn wound infection. Differenti-
ation between skin infection and colonisation should be
pointed out, as the presence of germs on the wound does not
necessarily mean that it is infected (see Appendix 1).
1.3. Dealing with local infection
Antibiotic therapy prescribed to prevent infection of burned
skin does not actually prevent it and even facilitates the
emergence of multi-resistant bacteria [10]. Diffusion of
antibiotic in the burned skin is questionable and cannot
achieve bactericidal concentrations so that bacteria can grow
and develop resistances. However, local topical agents are
known to be efcient in preventing and treating burned skin
infections [7]. For these two reasons, local infection that is,
without general symptoms of sepsis should require only
local treatment.
1.4. Role of bacterial population (inoculum)
The probability of antibiotic-resistant mutant strains appear-
ing withina bacterial population is not void. For example, with
Pseudomonas aeruginosa, the probability of a uoroquinolone-
resistant strain appearing is estimated at 10
6
. The risk of
appearance of resistant strains is therefore directly related to
the size of the bacterial population (inoculum). With P.
aeruginosa, if the size of the bacterial population exceeds
10
6
, the probability of a uoroquinolone-resistant strain
appearing becomes higher. One of the means of limiting this
probability is to reduce the inoculum [11]. For some infectious
diseases, the reduction of inoculum alone ensures recovery
b ur ns 3 7 ( 2 0 1 1 ) 1 6 2 6 17
without antibiotic therapy or becomes the main treatment
(this is especially the case of skin and soft-tissue infections
[12]). In burn patients, very signicant inocula may be
observed during pneumonias and/or infection of burned skin.
Inthese cases, reducing the inoculumhas tremendous impact,
by clearing for pneumonia and debridement (or removal) of
infected burned tissues, respectively.
During bacterial colonisation of tissue, the shift from
colonisation to infection depends on three parameters,
namely the level of the bacterial inoculum, host defences
and bacterial virulence [1315]. Reducing the inoculum may
therefore contribute to preventing infections.
2. Time for onset of antibiotic therapy
In case of serious infection (i.e., poorly tolerated and/or life
threatening), antibiotic therapy should be started within 6 h
following the diagnosis of infection [16,17] as delayed
antibiotic therapy increases mortality [1719]. When the
infection is not very serious (i.e., well-tolerated and without
organ failure), initiation of antibiotic therapy can be delayed
until microbiological documentation. In serious undocument-
ed infection, bacteriological sampling should be performed
before starting antibiotic therapy [20], but without delaying it.
As long as the infection is not documented, antibiotic
therapy is empiric. Therefore, broad-spectrum molecules
should be chosen for maximum efcacy. Nevertheless, the
choice for empiric treatment depends on patient ecology,
ward ecology, length of stay, previous antibiotic therapy,
patient condition, and so on.
3. Bactericidal or bacteriostatic molecules?
Burn patients exhibit immune deciency, which is still
incompletely understood, and mainly affects cell-mediated
immunity (lymphocytes, macrophages and neutrophils) [21].
In these conditions, antibiotic therapy will, by itself, probably
need to be effective, that is, without the help of host defences
[22]. Moreover, the infections observed are often with heavy
inoculae (lung, wound). Bactericidal antibiotics will there help
to reduce inoculum. Lastly, in case of serious infection,
antibiotic therapy will need to be effective quickly. For all
these reasons, bactericidal molecules should be preferred.
4. Association or monotherapy?
The literature does not provide powerful enough data to
recommend combination therapy rather than monotherapy
[23,24] except in particular cases. Nevertheless, combination
therapy has a number of theoretical advantages, namely
broader spectrum (useful in situations of empiric antibiotic
therapy), enhanced bactericidia (more important and with the
quickest bactericidal activity) and prevention of emergence of
resistant strains (especially when inoculum is heavy). The
probability of bacterial resistance to a combination of two
molecules is the product of probability for each molecule (if
each molecule presents with a probability of 10
6
, the
probability of the combination is 10
12
, which exceeds the
usual inoculae sizes).
Some antibiotics should not be used in monotherapy due
to their high selection risk (fosfomycin, fusidic acid, rifampi-
cin and uoroquinolones) [11]. Combination therapy is also
recommended against multi-resistant hospital bacteria to
avoid acquisition of new resistances, thereby maintaining
their sensitivity prole [11]. One should remember that the
burn patient is immunocompromised and expresses a
number of factors altering the pharmacokinetics of anti-
biotics [25]; this means that the regimen of antibiotics should
be altered when compared with that recommended in the
healthy volunteer [26]. Antibiotic therapy should be started
immediately and should be effective from the beginning
[11,12,16,17,19].
All these arguments are in favour of the use of antibiotic
combinations for the management of serious bacterial
infections in burn patients.
5. Adaptation of antibiotherapy
Adaptation is a two-stage strategy [19,27,28]:
Initial clinical approach: start of empirical treatment when
infection is suspected.
Subsequent bacteriological approach: assessment of initial
treatment based on bacteriological documentation.
Antibiotic therapy should be started immediately [16,17].
Consequently, it is often started though bacteriological
documentation is lacking (empiric antibiotic therapy). This
empiric antibiotic therapy may be inappropriate, andis known
to increase mortality [17,29]. The antibiotic usually chosen has
a broad-spectrum activity (with multi-drug resistant strains
selection risk) although bacteria involved are sensitive to
narrower-spectrum antibiotics [30,31]. In these conditions,
any antibiotic therapy should be assessed after 4872 h
[12,16,20], as soon as bacteriological results are available.
Antibiotic therapy will have to be adapted to the germ(s)
actually responsible for the infection.
Shifting frombroad-spectrumempiric antibiotic therapy to
a narrow-spectrum adapted strategy (guided by the antibio-
gram) is called de-escalation. It should be performed whenev-
er possible [16,20,27,28,32]. De-escalation has two aims,
namely individual benet (recovery of a patient) and collective
benet (reducing selective pressure and source of bacterial
resistance).
Three conditions are mandatory for de-escalation.
Bacteriological documentation available.
Antibiogram available (bacterial sensitivity to antibiotics
established).
Improvement of clinical status after 72 h.
There are understandable limits:
Reliability of bacteriological data (e.g., in the case of
ventilator-associated pneumonia, what type of sample
should be chosen to conrm diagnosis?).
b ur ns 3 7 ( 2 0 1 1 ) 1 6 2 6 18
How to assess the clinical evolution (e.g., which elements
should be used in pneumonia: hyperthermia? arterial blood
gases? imaging?)?
Discontinuation of antibiotic therapy considered useless
may be likened to de-escalation [33].
6. Duration of antibiotherapy
Excepted in few particular situations related to the microor-
ganism and/or severe immune failure, a well-conducted
antibiotic therapy enables a quick inoculum decrease [34].
Prolonged administration of antibiotics is often unjustied
and leads to an increase in selective pressure. Following
several prospective randomised studies conducted in ventila-
tor-associated pneumonia [32,35,36], antibiotic therapy lasting
78 days is recommended unless treatment provided initially
was adequate. However, in P. aeruginosa-related infections, a
longer duration is probably necessary [35]. In that case, it is
recommended not to exceed 15 days of antibiotic therapy [37]
or discontinue it after 4872 h of apyrexia (or disappearance of
signs that led to diagnosis of infection).
7. Administration methods (dosage and
rhythm of injection)
7.1. Notions of pharmacokinetics
In intensive care and burn patients, all pharmacokinetics
parameters (absorption, distribution, metabolism and excre-
tion) of many classes of drugs, including antimicrobials, are
altered, with signicant intra-individual variations, and have
been documented over the past 30 years [26,3844]. The main
clinical consequence is a drop in tissue concentrations. It has
also been demonstrated that low serum concentrations of
antibiotics mayleadtoboththerapeuticfailures andemergence
of resistant strains [45]. Inaddition, the resistance mechanisms
developed by bacteria lead to reduced efcacy of usual dosages
of antibiotic (increase in minimum inhibitory concentration),
and the combination of these factors brings about therapeutic
failures [46]. Consequently, theusuallyrecommendedregimen,
suitable for a healthy volunteer, is not recommended and both
daily dosage and regimen should be altered in burn patients.
7.2. Notions of pharmacodynamics
Bactericidal antibiotics may be divided into two groups,
depending on their bactericidal activity prole [47,48]:
Concentration-related antibiotics. Bactericidal activity is
proportional to the concentration obtained, that is, to the
administered dose: the higher the dose, the stronger the
bactericidal activity. The targeted pharmacokinetic objec-
tive is therefore the highest possible concentration, the only
limit being side effects.
Time-related antibiotics. Bactericidal activity increases with
the dose but reaches a plateau over which it does not
increase further (maximum bactericidal activity). With
these antibiotics, the determining factor is how long does
the concentration surpass the MIC.
7.3. Regimen
The regimen depends on the pharmacodynamic character-
istics of the molecules [47,49]:
Concentration-related antibiotics (aminoglycosides, uoroqui-
nolones and fosfomycin) [34,5054]. The parameter to
consider is the inhibitory quotient (IQ), dened as the ratio
between the maximum concentration (C
max
) and the MIC.
Administration is intermittent; the interval between two
administrations depends on the elimination half-life of the
molecule; it should not exceed 3 times this half-life [55].
Consequently, regimen of aminoglycosides is a single daily
dose (SDD) while, with uoroquinolones, it consists of
several daily injections (ciprooxacin 34 daily, ooxacin 3
daily, peoxacin 2 daily and levooxacin 23 daily).
Time-related antibiotics (beta-lactams, glycopeptides) [45,56
58]. Bactericidal activity is slow and poorly related to
concentration. The predictive parameter of therapeutic
success is the time during which the antibiotic serum
concentrations are above the MIC. The aim is therefore to
reach serum concentrations exceeding the MIC 100% of the
time. There are several methods to achieve this, namely
using molecules with a long half-life, shortening the time
period between the two injections or using continuous
intravenous infusion. Continuous infusion regimen seems
to be the optimal choice because it appears to provide more
stable serum levels in burn patients [5961]. Continuous
infusion needs the injection of a loading dose to achieve
levels above MIC within a reasonable time period. The
loading dose depends on the molecules used [12,16].
8. Monitoring antibiotic concentrations
Historically, antibiotic monitoring was suggested to prevent
toxicity. Nowadays, there is no doubt on its relevance in
guaranteeing, as soonas possible, the efcacy of the molecules
used [38,56,6264]. A new concept has been dened, based on
the interactions between the pharmacokinetics and pharma-
codynamics of the drug, in which the key factors are serum
levels. The following two situations occur, depending on the
bactericidal activity of the antibiotic considered:
Concentration-related activity: Achieving an IQ above 10 in
most cases [34,50] and above 20 for P. aeruginosa (or similar
germ)-related infection is recommended. To determine the
IQ, both C
max
and MIC values are requested. MIC of targeted
bacteria can be found by the bacteriology laboratory (E-test
or other technique [65]). When MIC is unknown, the highest
MIC in sensitive bacteria (low critical concentration (LCC))
can be found by local scientic societies or CDC and should
be the value used to calculate IQ.
To measure the maximum concentration (C
max
), sam-
pling should proceed 30 min after the end of the injection,
b ur ns 3 7 ( 2 0 1 1 ) 1 6 2 6 19
with the exception of ciprooxacin, where a sample must be
taken as soon as infusion is completed, due to the fast
diffusion of the molecule. With aminoglycosides, concen-
tration measurement just before the second injection
(through concentration) is recommended. It will help assess
the risk of toxicity.
Time-related antibiotics: When the continuous infusion regi-
men is chosen, monitoring blood concentrations by steady
state (C
ss
) is mandatory. The experts recommend a C
ss
between4 and 5 times the MIC[59]. Insome particular cases,
such as Pseudomonas infections, targeted C
ss
could be 10
times the MIC [57]. The half-life of most (except for
ceftriaxone, ertape ne` me, doripenem, ce fe pime and teico-
planin) is short. Provided that the steady state is reached
after 5 T1/2b, samples for C
ss
monitoring can be obtained by
the day following onset of the compound [59]. The steady
state is more quickly achieved after the administration of a
loading dose. Furthermore, with time-related antimicro-
bials, initiating continuous infusion without loading dose
will probably lead to initial low concentrations, when
inoculum and thereby risk of resistance selection is higher.
In the continuous infusion regimen, the sample can be
obtained for monitoring at any moment when the steady
state is thought to be achieved.
9. Perioperative antibiotic prophylaxis
In burn patients, antibiotic prophylaxis is only relevant during
the perioperative period as discussed above [10]. It aims to
full three objectives [66,67]:
Reduce local inoculum and enhance grafts intake.
Decrease wound-borne bacteraemia.
Do not increase selection pressure.
Antibiotic prophylaxis rules had been dened and spread
worldwide by several consensus conferences driven by other
scientic societies [68]. These are:
Antibiotic prophylaxis shouldbe startedearly enoughbefore
surgery (approximately 1 h 30 min, usually just before
anaesthesia induction).
Half of the initial dose should be re-injected every 2 half-
lives of the molecule (for oxacillin, the re-injectionshould be
practised every 4 h).
Antibiotic prophylaxis lasts at least 24 h and should never
exceed 48 h.
If repeated injections are likely, continuous infusion after
loading dose is possible, provided pharmacodynamics of the
molecule is suitable (time-related bactericidal molecules).
10. Guidelines from the French Society for
Burn Injuries (SFETB)
The following guidelines have been established according to
the levels of evidence-based medicine [1,2]. They have been
validated by Socie te Franc aise dEtude et de Traitement des
Bru lures in June 2008. They are available at www.sfetb.org or
www.brulure.org.
10.1. Guidelines for antibiotic therapy
No antibiotics without proven infections (level 1)
A local infection requires a local treatment (level 1)
However, when the local infection is associated with
general signs of infection, experts consider that the
infectious process is no longer purely local and that use
of an antibiotic may be indicated.
Attempt to reduce the bacterial inoculum (level 5)
Antibiotics in serious infections is an emergency (level 1)
Use bactericidal antibiotics (level 5)
Know how to combine antibiotics (level 5)
Experts recommend the use of antibiotic combinations
for the management of serious bacterial infections
during, at least, the rst 72 h of the infection.
Adapt antibiotic therapy (level 1)
Any antibiotic therapy should be assessed within 48
72 h, as soon as bacteriology is available. Antibiotic
therapy should be adapted to the germ(s) responsible of
the infection.
Practise de-escalation (level 5)
Anytime possible, shift broad-spectrum antibiotic for
narrow-spectrum one guided by the antibiogram.
When to stop antibiotics therapy (level 5)
Antibiotic therapy lasting 78 days is recommended,
provided initial treatment was accurate.
In P. aeruginosa infections antibiotherapy should not
exceed 15 days.
Respect the regimen (level 1)
With concentration-related antibiotics, administration is
intermittent and the interval between two injections
should not exceed 3 times its half-life.
With time-related antibiotics, continuous infusion after
the loading dose should be used.
In any burn patient, but those with kidney and/or liver
failure, higher dosage than usually recommended is
needed.
Antibiotic monitoring is mandatory (level 2)
With concentration-related antibiotics, IQover 10 should
be achieved (20 in P. aeuginosa infections).
With time-related antibiotics, experts recommend to
achieve a concentration at steady state between 4 and 5
times the MIC.
10.2. Guidelines for antibiotics prophylaxis
In burn patients, antibiotic prophylaxis could be used in
patients needing invasive surgery (excisions, aps, etc.) but
not in dressing changes. The experts recommend [68] (level 5):
No identied local infection and undened bacterial target.
Target methicillin-sensitive Staphylococcus, that is, oxa-
cillin or cloxacillin (30 mg kg
1
) or rst-generation ceph-
alosporin (30 mg kg
1
). In case of allergy, clindamycin
should be used (10 mg kg
1
).
No identied local infection but isolation of a pathogen on
skin samples.
b ur ns 3 7 ( 2 0 1 1 ) 1 6 2 6 20
Target this one.
Documented or non-documented local infection.
This is no longer prophylaxis, as the infection is ongoing.
Administration should follow the usual rules about
curative treatment and consider the identied or
presumed pathogen.
Application of inert skin substitute such as articial dermis.
In the absence of guidelines in the literature, the experts
suggest if bacteria are isolated from skin samples, target
them. Otherwise, target Staphylococcus.
10.3. Practical use
For examples of regimen for some antibiotics in burn patients,
see Appendix 2.
Conict of interest statement
The authors have no nancial interests to declare.
Appendix A
General denitions
No predictive value of infection
In adults, presence of SIRS: two or more criteria of the four
below:
T (8C)>38.5 8C or <36 8C,
Heart rate >90 bpm,
RR >20 per minute or capnia <25 mmHg,
Leucocytes >12 G or <4 G or >10% of immature forms.
Any burn patient >20% BSA and/or with smoke inhalation
injury is likely to present with SIRS criteria in any infectious
process.
Predictive values of infection
Appearance of SIRS criteria in an adult whose lesions are
<15% or 20% BSA and without any smoke inhalation injury.
Twoor more of the four criteria belowinanadult witha burn
>BSA and/or with smoke inhalation injury:
- T (8C) >39.5 8C or <35.5 8C,
- 50% basal HR,
- 50% basal RR,
- or 100% of number of leucocytes,
- Haemodynamic failure with onset or enhancement of
catecholamine treatment.
Denitions of infection criteria for burned skin
The diagnosis of a skin infection is clinical.
Bacterial infection
(1) Positive local signs:
Presence of a local or loco-regional inammatory
reaction
Unfavourable and unexpected local evolution
To the burns
- Presence of pus
- Rapid cleansing and detachment
- Appearance of blackish marks (necrosis or haemor-
rhage)
- Unexplained conversion of a lesion from supercial to
deep (>48th hour)
To the donor graft sites
- Presence of pus
- Unexplained delayed healing
- Scab
To the recipient grafts
- Presence of pus
- Lysis of grafts
- Necrosis of fat located under the graft
To the healed areas
- Impetigo
- Lysis of healed areas
(2) Bacteriological skin samples:
They are used to nd out the germ(s) involved.
More often, a simple swab is enough.
The biopsy is never systematic. It might be performed in
difcult cases, followed by
Microbiology examination
- Direct microscope examination with staining and
semi-quantitative measurement of germs
- Quantication of germs present per gram of tissue
after homogenate status: threshold of 10
5
CFU g
1
is
retained as signicant of the risk of haematogenous
dissemination
An extemporaneous pathology examination after
freezing enabling one to appreciate the level of
invasivity
- Colonisation: germs in the non-vascularised tissue
- Infection: germs in the living tissue and in contact with
vessels
(3) Summary:
Skin infection with general signs is considered as a
systemic infection originated from skin.
General signs + + + +
Local signs + + + +
Skin culture + + + +
Skin infection + S + S + ? +
Fungal skin infection
The diagnosis may be conrmed with a biopsy.
Herpes skin infection
The diagnosis is clinical and may be conrmed with the
onset of a serology conversion and the presence of the virus in
local samples.
Denitions of infection criteria for the other sites
Denitions per site (below) originate from those main-
tained by the CCLIN (French Central Comity for Struggle
b ur ns 3 7 ( 2 0 1 1 ) 1 6 2 6 21
Against Nosocomial Infections), the survey of the REA-
REACAT/RAISIN 2006 monitoring network. These denitions
are taken up in the Guide de de nition des infections
nosocomiales of the CCLIN Paris-Nord (1995), itself adapted
from 1988 CDC denitions (CDC denitions for nosocomial
infections, Gardner JS, Jarvis WR, Emori TG, et al., Am J Infect
Contl 1988;16:12840.) and the 1992 CSHPF (100 recommanda-
tions pour la surveillance et la pre vention des infections, BEH
June 1992) (100 guidelines for the monitoring andpreventionof
infections).
Lung infection
Pneumonia
General signs + specic organ signs microbiological cri-
teria:
At least two chest X-rays, withnewimage of pneumonia or a
change of a previous image
At least one of the following signs (two in the absence of
microbiological criteria):
- Appearance of purulent secretions or change in their
characteristics (colour, smell, consistency and
quantity)
- Dyspnoea, tachypnoea or cough (if not ventilated)
- Recent onset or worsened hypoxemia
Microbiological diagnosis (one of the following criteria):
- BAL with a threshold of 10
4
CFU ml
1
or 5% of cells with
direct bacterial inclusion
- Wimberley brush technique with a threshold of
10
3
CFU ml
1
- PDP with threshold of 10
3
CFU ml
1
- Quantitative bronchial aspiration with a threshold of
10
6
CFU ml
1
- Blood culture or positive sample of bronchial tissue
(histology) or pleural uid in the absence of any other
source of infection
- Specic examinations for viral pneumonia or pneumonia
due to particular microorganisms (Ag or Ac in bronchial
secretions, direct examinations or positive cultures of
bronchial secretions, urinary antigens or serology con-
versions)
Bronchitis
General signs, cough, recent change in expectorations or
bronchial aspirations, bronchial crepitations + isolation of
germ(s) in bronchial aspirations + no radiological sign of
infection.
Bacteraemia
General signs + positive blood culture(s):
At least one blood culture (sample taken during a tempera-
ture peak) positive to a germ known to be a pathogen
Two blood cultures in a maximum interval of 48 h
(sample taken during a temperature peak) positive to one
of the following germs: coagulase-negative Staphylococcus,
Bacillus sp., Corynebacterium sp., Propionibacterium sp., Micro-
coccus sp. and Acinetobacter sp.
If bacteraemia is the consequence of another infection or is
responsible for secondary localisations, local signs of
infection will be associated.
In case of central venous catheter (CVC)-associated bacter-
aemia, the following will be necessary:
- Positive blood culture in presence of a CVC (or withdrawn
within 48 h) in the absence of any other infection to the
same germ
- AND one of the following criteria:
- 10
3
CFU ml
1
of the same germ in quantitative culture of
the catheter
- Differential blood cultures with CVC/periph 5 or positiv-
ity time period CVC/periph 2 h to the same germ.
Infection of central catheter
Local or general infection signs with all the following
criteria:
No blood culture to the same germ
CVC culture 10
3
CFU ml
1
Regression of the infectious syndrome within 48 h following
catheter withdrawal
Urinary tract infection
Positive urine cytology (10
4
leucocytes ml
1
)
Asymptomatic (without general signs):
- Bladder catheter within past 7 days: urine culture
10
5
CFU ml
1
if the patient has had urinary catheter
insertion within the previous 7 days.
- In the absence of urinary catheterisation, no bladder
catheter: two consecutive urine cultures 10
5
CFU ml
1
to
the same germ(s) without the presence of more than two
species (no more than two different species)
Symptomatic (general signs):
- Urine culture 10
5
CFU ml
1
(at maximum of two species)
or
- or 10
3
CFU ml
1
with 10
4
leukocytes ml
1
and general
signs
Appendix B
Methods of administration of some antibiotics in burn
patients.
Beta-lactams
Beta-lactams are time-related bactericidal antibiotics.
They should be administered by continuous infusion
whenever possible [55,6973].
Continuous perfusion is immediately preceded by a
loading dose, depending on the molecule [12,16], and is
usually equal to a single dose in repeated administration
regimen.
Continuous administration is sometimes rendered difcult
by poor stability of the molecule along time (clavulanic acid
and imipenem), physical and chemical incompatibility of
molecules and differences in the pharmacokinetics of a
molecule and its co-factor (amoxicillinclavulanic acid/imi-
penemcilastatin).
b ur ns 3 7 ( 2 0 1 1 ) 1 6 2 6 22
Penicillins
Cloxacillin and oxacillin
Continuous infusion
150200 mg kg
1
daily
Loading dose 50 mg
1
kg
1
Targeted steady-state concentration is at 810 mg l
1
or 45 times
the MIC.
Amoxicillin, amoxicillin + clavulanate
Continuous infusion
150200 mg kg
1
daily
Loading dose 50 mg
1
kg
1
Targeted steady-state concentration is at 6480 mg l
1
or 45 times
the MIC.
Amoxicillin: stable 6 h at 25 8C in NaCl solvent. In case of electric
syringe administration, replace the syringe every 6 h.
Amoxicillinclavulanate: clavulanate tends to accumulate because
its half-life is longer than amoxicillins. In continuous infusion
regimen, mix 50% amoxicillin and 50% as amoxicillinclavulanate
and change syringe every 6 h. In repeated injections regimen, the
recommended targeted concentration (1620 mg l
1
) is a trough
concentration.
Carboxy- and Ureidopenicillins
Ticarcillin, ticarcillin + clavulanic acid
Continuous infusion
150200 mg kg
1
daily
Loading dose 50 mg
1
kg
1
Targeted steady-state concentration 6480 mg l
1
or 45 times the
MIC
Ticarcillin: stable for 24 h at 25 8C
Ticarcillinclavulanic acid: stable for 6 h at 25 8C. Clavulanate tends to
accumulate because its half-life is longer than ticarcillins. In
continuous infusion regimen, mix 50% ticarcillin and 50% ticarcil-
linclavulanate and change syringe every 6 h. In repeated injections
regimen, the recommended target concentration (1620 mg l
1
) is a
trough concentration
Piperacillin, piperacillin + tazobactam
Continuous infusion
At least 200 mg kg
1
daily
Loading dose 50 mg kg
1
There are no stability or accumulation problems. Targeted steady-
state concentration is reached at 6480 mg l
1
or 45 times the MIC
Cephalosporins
Cefotaxime
Continuous infusion
100150 mg kg
1
daily
Loading dose 25 mg kg
1
Stability: 3 h 30 min at 25 8C
Targeted steady-state concentration is at 1620 mg l
1
or 45 times
MIC
Ceftazidime
Continuous infusion
100150 mg kg
1
daily
Loading dose 25 mg kg
1
Administration in soft bags with volumetric pump is preferred due
to the risk of gas release, but continuous administration with electric
syringe is possible
Targeted steady-state concentration is at 1620 mg l
1
or 45 times
MIC. For germs at risk (specically ticarcillin-R P. aeruginosa), the
targeted steady-state concentration is 3240 mg l
1
or 810 times MIC
Iimipenem
Continuous infusion
50100 mg kg
1
daily
Loading dose 10 mg kg
1
Stability: 3 h 30 min at 25 8C
Targeted steady-state concentration is at 1620 mg l
1
or 45 times
MIC. For germs at risk (specically Acinetobacter baumanii) it is 32
40 mg l
1
or 810 times MIC
Fluoroquinolones
Concentration-related bactericidal antibiotics active on
Gram-negative and Gram-positive bacteria [74]. These pro-
ducts should be administered repeatedly. The frequency of
injections is determined by the half-life of the molecules [74].
Only few data about pharmacokinetics of uoroquinolones
such as ciprooxacin being available, the experts can only
provide guidelines for ciprooxacin.
Ciprooxacin [26,75]
Repeated administration
34 injections daily
1020 mg kg
1
per injection (total dose 3080 mg kg
1
daily)
Infuse for 30 min. Sample for C
max
immediately at the end of the
injection (due to the very quick diffusion time of the molecule)
Target (C
max
): >30 mg l
1
(optimal = 40 mg l
1
) or >10 times the
MIC
Beware of occult water administration (0.5 ml per mg ciproox-
acin)
Aminoglycosides
Concentration-related bactericidal antibiotics.
Single daily dose (SDD).
The dosage should be increased in burn patients [42].
Amikacin
30 mg kg
1
once a day
Infuse for 60 min
Sample for peak concentration 30 min after the end of infusion
Targeted peak value: >80 mg l
1
or >10 times the MIC
Sample for trough concentration immediately before the second
infusion
Trough concentration < 5 mg l
1
Gentamicin, tobramycin and netilmicin
10 mg kg
1
once a day
Infuse for 60 min
Sample for peak concentration 30 min after the end of infusion
Targeted peak value: >20 mg l
1
or >10 times the MIC
Sample for trough concentration immediately before the second
infusion
Trough concentration < 2 mg l
1
Glycopeptides
Vancomycin
Continuous infusion
30 mg kg
1
per day
Loading dose = 5 mg kg
1
Concentration at steady state: 2030 mg l
1
. Sample can be taken
any time, more than 12 h after infusion onset
b ur ns 3 7 ( 2 0 1 1 ) 1 6 2 6 23
Oxazolidinones
Linezolide
a
Spectrum limited to Gram-positive cocci. Bactericidal activity
limited to streptococci [76].
Continuous infusion (time-related bactericidal activity)
1200 mg daily in adults
Loading dose = 5 mg kg
1
Target concentration is 10 mg l
1
or 5 times the MIC
a
Few data available by this day [7779].
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