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Review
Antibiotics and the burn patient
Francois Ravata,*, Ronan Le-Floch b, Christophe Vinsonneau c, Pierre Ainaud d,Marc Bertin-Maghite, HerveCarsinf, Gerard Perro g
the SocieteFrancaise dEtude et de Traitement des Brulures (SFETB)aCentre des brules, Centre hospitalier St Joseph et St Luc, 20 quai Claude Bernard, 69007 Lyon, Franceb Centre des brules, Centre hospitalo-universitaire, Nantes, FrancecCentre des brules, Groupe hospitalier Cochin, Paris, Franced Centre des brules, Hopital de la Conception, Marseille, Francee Centre des brules, Hopital Edouard Herriot, Lyon, FrancefCentre des brules, Hopital dInstruction des Armees Percy, Clamart, FrancegCentre des brules, Hopital Pellegrin-Tripode, Bordeaux, France
Contents
1. General considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171.1. 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
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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 shouldnot be misused. With this aimin mind, thefollowing 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:[email protected](F. Ravat).
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
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
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without antibiotic therapy or becomes the main treatment
(this is especially the case of skin and soft-tissue infections
[12]). In burn patients, very significant inocula may be
observed during pneumonias and/or infection of burned skin.
In these cases, reducing theinoculum hastremendous impact,
by clearing for pneumonia and debridement (or removal) of
infected burned tissues, respectively.
During bacterial colonisation of tissue, the shift fromcolonisation 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 withoutorgan 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 efficacy. 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 deficiency, 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 106, the
probability of the combination is 1012, 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 fluoroquinolones)[11]. Combination therapy is also
recommended against multi-resistant hospital bacteria to
avoid acquisition of new resistances, thereby maintaining
their sensitivity profile[11]. One should remember that theburn 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 therapymay be inappropriate, andis known
to increase mortality [17,29]. The antibiotic usually chosen hasa 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 from broad-spectrum empiric 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 benefit (recovery of a patient) and collective
benefit (reducing selective pressure and source of bacterialresistance).
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 confirm diagnosis?).
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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 unjustified
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 andrhythm 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 significant intra-individual variations, and havebeen 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 maylead to boththerapeuticfailures andemergence
of resistant strains [45]. In addition, the resistance mechanisms
developed by bacteria lead to reduced efficacy of usual dosages
of antibiotic (increase in minimum inhibitory concentration),
and the combination of these factors brings about therapeutic
failures [46]. Consequently,the usually recommended regimen,
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 profile[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, fluoroqui-
nolones and fosfomycin) [34,5054]. The parameter to
consider is the inhibitory quotient (IQ), defined as the ratio
between the maximum concentration (Cmax) 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 fluoroquinolones, it consists of
several daily injections (ciprofloxacin 34 daily, ofloxacin 3
daily, pefloxacin 2 daily and levofloxacin 23 daily).
Time-related antibiotics (beta-lactams, glycopeptides) [45,5658]. 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. Theloading 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 soon as possible,the efficacy of the molecules
used[38,56,6264]. A new concept has been defined, 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, bothCmaxand 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 scientific societies or CDC and should
be the value used to calculate IQ.
To measure the maximum concentration (Cmax), sam-
pling should proceed 30 min after the end of the injection,
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with the exception of ciprofloxacin, 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 steadystate (Css) is mandatory. The experts recommend a Cssbetween4 and 5 timesthe MIC [59]. In some particularcases,
such as Pseudomonas infections, targeted Css could be 10
times the MIC [57]. The half-life of most (except for
ceftriaxone, ertapeneme, doripenem, cefepime and teico-
planin) is short. Provided that the steady state is reached
after 5 T1/2b, samples forCssmonitoring 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
fulfil 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 defined and spread
worldwide by several consensus conferences driven by other
scientific societies[68]. These are:
Antibiotic prophylaxisshould be started earlyenough before
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-injection shouldbe
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 pharmacodynamicsof the
molecule is suitable (time-related bactericidal molecules).
10. Guidelines from the French Society forBurn Injuries (SFETB)
The following guidelines have been established according to
the levels of evidence-based medicine[1,2]. They have been
validated by Societe Francaise dEtude et de Traitement des
Brulures in June 2008. They are available atwww.sfetb.orgor
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 withgeneral 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 first 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. Antibiotictherapy 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 injectionsshould 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, IQ over 10 should
be achieved (20 in P. aeuginosainfections).
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, flaps, etc.) but
not in dressing changes. The experts recommend[68](level 5):
No identified local infection and undefined bacterial target.
Target methicillin-sensitive Staphylococcus, that is, oxa-
cillin or cloxacillin (30 mg kg1) or first-generation ceph-
alosporin (30 mg kg1). In case of allergy, clindamycin
should be used (10 mg kg1).
No identified local infection but isolation of a pathogen on
skin samples.
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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 identified or
presumed pathogen.
Application of inert skin substitute such as artificial dermis.
In the absence of guidelines in the literature, the expertssuggest 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,
seeAppendix 2.
Conflict of interest statement
The authors have no financial interests to declare.
Appendix A
General definitions
No predictive value of infection
In adults, presence of SIRS: two or more criteria of the four
below:
T(8C)>38.5 8C or 90 bpm,
RR >20 per minute or capnia 12 G or 10% of immature forms.
Any burn patient >20% BSA and/or with smoke inhalationinjury 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
BSA and/or with smoke inhalation injury:
- T(8C) >39.5 8C or 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 find out the germ(s) involved.
More often, a simple swab is enough.The biopsyis never systematic.It might be performedin
difficult cases, followed by
Microbiology examination
- Direct microscope examination with staining and
semi-quantitative measurement of germs
- Quantification of germs present per gram of tissue
after homogenate status: threshold of 105 CFU g1 is
retained as significant 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 confirmed with a biopsy.
Herpes skin infection
The diagnosis is clinical and may be confirmed with the
onset of aserology conversion and the presence of the virus in
local samples.
Definitions of infection criteria for the other sites
Definitions per site (below) originate from those main-
tained by the CCLIN (French Central Comity for Struggle
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Against Nosocomial Infections), the survey of the REA-
REACAT/RAISIN 2006 monitoring network. These definitions
are taken up in the Guide de definition des infections
nosocomiales of the CCLIN Paris-Nord (1995), itself adapted
from 1988 CDC definitions (CDC definitions 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 prevention des infections, BEHJune 1992) (100 guidelines for the monitoring and prevention of
infections).
Lung infection
Pneumonia
General signs + specific organ signs microbiological cri-
teria:
Atleast two chestX-rays, with new image ofpneumonia 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 theircharacteristics (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 104 CFU ml1 or 5% of cells with
direct bacterial inclusion
- Wimberley brush technique with a threshold of
103 CFU ml1
- PDP with threshold of 103 CFU ml1
- Quantitative bronchial aspiration with a threshold of
106 CFU ml1
- Blood culture or positive sample of bronchial tissue(histology) or pleural fluid in the absence of any other
source of infection
- Specific 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., Corynebacteriumsp., Propionibacterium sp., Micro-
coccussp. andAcinetobactersp.
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:
- 103 CFU ml1 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 103 CFU ml1
Regression of the infectious syndrome within 48 h following
catheter withdrawal
Urinary tract infection
Positive urine cytology (104 leucocytes ml1)
Asymptomatic (without general signs):
- Bladder catheter within past 7 days: urine culture
105 CFU ml1 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 105 CFU ml1 to
the same germ(s) without the presence of more than two
species (no more than two different species)
Symptomatic (general signs):
- Urine culture 105 CFU ml1 (at maximum of two species)
or- or 103 CFU ml1 with 104 leukocytes ml1 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 difficult
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).
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Penicillins
Cloxacillin and oxacillin
Continuous infusion
150200 mg kg1 daily
Loading dose 50 mg1 kg1
Targeted steady-state concentration is at 810 mg l1 or 45 times
the MIC.
Amoxicillin, amoxicillin + clavulanate
Continuous infusion
150200 mg kg1 daily
Loading dose 50 mg1 kg1
Targeted steady-state concentration is at 6480 mg l1 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 l1) is a trough
concentration.
Carboxy- and Ureidopenicillins
Ticarcillin, ticarcillin + clavulanic acid
Continuous infusion
150200 mg kg1 daily
Loading dose 50 mg1 kg1
Targeted steady-state concentration 6480 mg l1 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 l1) is a
trough concentration
Piperacillin, piperacillin + tazobactam
Continuous infusion
At least 200 mg kg1 daily
Loading dose 50 mg kg1
There are no stability or accumulation problems. Targeted steady-
state concentration is reached at 6480 mg l1 or 45 times the MIC
Cephalosporins
Cefotaxime
Continuous infusion
100150 mg kg1 daily
Loading dose 25 mg kg
1
Stability: 3 h 30 min at 25 8C
Targeted steady-state concentration is at 1620 mg l1 or 45 times
MIC
Ceftazidime
Continuous infusion
100150 mg kg1 daily
Loading dose 25 mg kg1
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 l1 or 45 times
MIC. For germs at risk (specifically ticarcillin-R P. aeruginosa), the
targeted steady-state concentration is 3240 mg l1 or 810 times MIC
Iimipenem
Continuous infusion
50100 mg kg1 daily
Loading dose 10 mg kg1
Stability: 3 h 30 min at 25 8C
Targeted steady-state concentration is at 1620 mg l1 or 45 times
MIC. For germs at risk (specifically Acinetobacter baumanii) it is 32
40 mg l1 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 fluoroquinolones
such as ciprofloxacin being available, the experts can only
provide guidelines for ciprofloxacin.
Ciprofloxacin [26,75]
Repeated administration
34 injections daily1020 mg kg1 per injection (total dose 3080 mg kg1 daily)
Infuse for 30 min. Sample for Cmaximmediately at the end of the
injection (due to the very quick diffusion time of the molecule)
Target (Cmax): >30 mg l1 (optimal = 40 mg l1) or >10 times the
MIC
Beware of occult water administration (0.5 ml per mg ciproflox-
acin)
Aminoglycosides
Concentration-related bactericidal antibiotics.
Single daily dose (SDD).
The dosage should be increased in burn patients[42].
Amikacin
30 mg kg1 once a day
Infuse for 60 min
Sample for peak concentration 30 min after the end of infusion
Targeted peak value: >80 mg l1 or >10 times the MIC
Sample for trough concentration immediately before the second
infusion
Trough concentration < 5 mg l1
Gentamicin, tobramycin and netilmicin
10 mg kg1 once a day
Infuse for 60 min
Sample for peak concentration 30 min after the end of infusion
Targeted peak value: >20 mg l1 or >10 times the MIC
Sample for trough concentration immediately before the second
infusion
Trough concentration < 2 mg l1
Glycopeptides
Vancomycin
Continuous infusion
30 mg kg1 per day
Loading dose = 5 mg kg1
Concentration at steady state: 2030 mg l1. Sample can be taken
any time, more than 12 h after infusion onset
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Oxazolidinones
Linezolidea
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 kg1
Target concentration is 10 mg l1 or 5 times the MICa Few data available by this day[7779].
r e f e r e n c e s
[1] Sackett DL, Straus SE, Richardson WS, Rosenberg W,Haynes RB. Evidence-based medicine: how to practice andteach EBM, second ed., London: Churchill Livingstone;2000.
[2] Delvenne C, Pasleau F. Comment resoudre en pratique unprobleme diagnostique ou therapeutique en suivant unedemarche EBM? Rev Med Liege 2000;55:22632.
[3] Kollef MH. Is there a role for antibiotic cycling in theintensive care unit? Crit Care Med 2001;28(Suppl. 4):N13542.
[4] Goldmann DA, Weinstein RA, Wenzel RP, Tablan OC,Dumas RJ, Gaynes RP, et al. Strategies to prevent andcontrol the emergence and spread of antimicrobialresistant microorganisms in hospitals: a challenge tohospital leadership. JAMA 1996;275:23440.
[5] Haute Autoritede Sante. Recommandationsprofessionnelles: strategies dantibiotherapie et preventiondes resistances bacteriennes en etablissement de sante;Avril 2008.www.has.fr.
[6] Latarjet J, Echinard C. Les brulures. Paris: Masson; 1993.[7] Heggers JP, Hawkins H, Edgar P, Villareal C, Herndon D.
Treatment of infection in burns. In: Herndon DH, et al.,
editors. Total burn care. second ed., London: WB Saunders;2002. p. 12069.
[8] Sherwood ER, Traber DL. The systemic inflammatoryresponse syndrome. In: Herndon DH, editor. Total burncare. 3rd ed, Saunders-Elsevier; 2007. p. 293309.
[9] Jeschke MG, Mlcak RP, Finnerty CC, Norbury WB, GauglitzGG, Kulp GA, et al. Burn size determines the inflammatoryand hypermetabolic response. Crit Care Med2007;35(Suppl.):S51923.
[10] Ugburo AO, Atoyebi OA, Oyeneyin JO, Sowemimo GOA. Anevaluation of the role of systemic antibiotic prophylaxis inthe control of burn wound infection at the Lagos UniversityTeaching Hospital. Burns 2004;30:438.
[11] Conference dexperts de la SFAR (Societe FrancaisedAnesthesie et de Reanimation). Associations
dantibiotiques ou monotherapie en reanimationchirurgicale et en chirurgie; 1999. www.sfar.org.
[12] Antibiotherapie probabiliste des etats septiques, graves.Ann Fr Anesth Reanim 2004;23:10206.
[13] Lepape A. Epidemiologie et ecologie bacterienne desinfections nosocomiales en reanimation. In: Martin C, GouinF, editors. Infections et antibiotherapie en reanimation auxurgences et en chirurgie. Paris: Arnette; 2000. p. 42739.
[14] Greene JN. The microbiology of colonization, includingtechniques for assessing and measuring colonization.Infect Contl Hosp Epidemiol 1996;17:1148.
[15] Bonten MJ, Weinstein RA. The role of colonization in thepathogenesis of nosocomial infections. Infect Contl HospEpidemiol 1996;17:193200.
[16] Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T,
Cohen J, et al. Surviving. Sepsis Campaign guidelines for
management of severe sepsis and septic shock. IntensiveCare Med 2004;30:53655.
[17] Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S,et al. Duration of hypotension before initiation of effectiveantimicrobial therapy is the critical determinant of survivalin human septic shock. Crit Care Med 2006;34:158996.
[18] Luna CM, Vujacich P, Niederman MS, Vay C, Gherardi C,Matera J, et al. Impact of BAL data on the therapy and
outcome of ventilator-associated pneumonia. Chest1997;111:67685.
[19] Iregui M, Ward S, Sherman G, Fraser VJ, Kollef MH. Clinicalimportance of delays in the initiation of appropriatetreatment for ventilator-associated pneumonia. Chest2002;122:2628.
[20] Kollef MH, Micek ST. Strategies to prevent antimicrobialresistance in the intensive care unit. Crit Care Med2005;33:184553.
[21] Munster AM. The immunological response and strategiesfor intervention. In: Herndon DH, et al., editors. Total burncare. second ed., London: WB Saunders; 2002. p. 31630.
[22] Zhao X, Drlica K. Restricting the selection of antibiotic-resistant mutants: a general strategy derived fromfluoroquinolones studies. Clin Infect Dis 2001;33(Suppl.
3):S14756.[23] Brun-Buisson C. Associations dantibiotiques ou
monotherapie?In: Actualites en Reanimation et Urgences.Paris: Elsevier Masson; 2007. pp. 463473.
[24] Safdar N, Handelsman J, Maki DG. Does combinationantimicrobial therapy reduce mortality in Gram-negativebacteraemia? A meta-analysis. Lancet Infect Dis2004;4:51927.
[25] Blanchet B, Julien V, Vinsonneau C, Tod M. Influence ofburns on pharmacokinetics and pharmacodynamics ofdrugs used in the care of burn patients. Clin Pharmacokinet2008;47:63554.
[26] Lesne-Hulin A, Bourget P, Ravat F, Goudin C, Latarjet J.Clinical pharmacokinetics of ciprofloxacin in patients withmajor burns. Eur J Clin Pharmacol 1999;55:5159.
[27] Rello J, Vidaur L, Sandiumenge A, Rodriguez A, Gualis B,Boque C, et al. De-escalation therapy in ventilator-associated pneumonia. Crit Care Med 2004;32:218390.
[28] Hoffken G, Niederman MS. Nosocomial pneumonia: theimportance of a de-escalating strategy for antibiotictreatment of pneumonia in the ICU. Chest 2002;122:214832196.
[29] Dupont H, Mentec H, Sollet JP, Bleichner G. Impact ofappropriateness of initial antibiotic therapy on theoutcome of ventilator-associated pneumonia. IntensiveCare Med 2001;27:35562.
[30] Kollef MH. Optimizing antibiotic therapy in the intensivecare unit setting. Crit Care 2001;5:18995.
[31] Kollef MH. Gram negative bacterial resistance: evolvingpatterns and treatment paradigms. Clin Inf Dis
2005;40(Suppl. 2):S8588.[32] Micek ST, Heuring TJ, Hollands JM, Shah RA, Kollef MH.
Optimizing antibiotic treatment for ventilator-associatedpneumonia. Pharmacotherapy 2006;26(2):20413.
[33] Kollef MH, Kollef KE. Antibiotic utilization and outcomesfor patients with clinically suspected ventilator-associatedpneumonia and negative quantitative BAL culture results.Chest 2005;128:270613.
[34] Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC,Schentag JJ. Pharmacodynamics of intravenousciprofloxacin in seriously ill patients. Antimicrob AgentsChemother 1993;37:107381.
[35] Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, WermertD, et al. Comparison of 8 vs 15 days of antibiotic therapy forventilator associated pneumonia in adults: a randomized
trial. JAMA 2003;290:258898.
b u r n s 3 7 ( 2 0 1 1 ) 1 6 2 624
http://www.has.fr/http://www.has.fr/http://www.sfar.org/http://www.sfar.org/http://www.sfar.org/http://www.has.fr/ -
8/11/2019 Antibiotics and the Burn Patient
10/11
[36] Christ-Crain M, Stolz D, Bingisser R, Muller C, Miedinger D,Huber PR, et al. Procalcitonin guidance of antibiotic therapyin community-acquired pneumonia: a randomized trial.Am J Respir Crit Care Med 2006;174(1):8493.
[37] Guidelines for the management of adults with hospital-acquired ventilator-associated and healthcare-associated,pneumonia. Am J Resp Crit Care Med 2005;171:388416.
[38] Potel G, Caillon J, Jacqueline C, Navas D, Kergueris MF,
Batard E. Dosage des antibiotiques en reanimation: quandet comment demander et interpreter les tests. Reanimation2006;15:18792.
[39] Weinbren MJ. Pharmacokinetics of antibiotics in burnpatients. J Antimicrob Chemother 1999;44:31927.
[40] Zaske DE, Sawchuk RJ, Gerding DR, Strate RG. Increaseddosage requirements of gentamycin in burn patients. JTrauma 1976;6:8248.
[41] Bourget P, Lesne-Hulin A, Le ReveilleR, Le Bever H, CarsinH. Clinical pharmacokinetics of piperacillintazobactamcombination in patients with major burns and signsof infection. Antimicrob Agents Chemother 1996;40:13945.
[42] Conil JM, Georges B, Breden A, Segonds C, Lavit M, Seguin T,et al. Increased amikacin dosage requirements in burn
patients receiving a once-daily regimen. Int J AntimicrobAgents 2006;28:22630.
[43] Kiser TH, Hoody DW, Obritsch MD, Wegzyn CO, Bauling PC,Fish DN. Levofloxacin pharmacokinetics andpharmacodynamics in patients with severe burn injury.Antimicrob Agents Chemother 2006;50:193745.
[44] Mohr 3rd JF, Ostrosky-Zeichner L, Wainright DJ, Parks DH,Hollenbeck TC, Ericsson CD. Pharmacokinetic evaluation ofsingle-dose intravenous daptomycin in patients withthermal burn injury. Antimicrob Agents Chemother2008;52:18913.
[45] Craig W. Does the dose matter? Clin Infect Dis2001;33(Suppl. 3):S2337.
[46] Roberts JA, Kruger P, Paterson DL, Lipman J. Antibioticresistancewhats dosing got to do with it? Crit Care Med
2008;36:243340.[47] Petitjean O, Nicolas P, Tod M. Pharmacodynamie des
antibiotiques. In: Martin C, Gouin F, editors. Infections etantibiotherapie en reanimation aux urgences et enchirurgie. Paris: Arnette; 2000. p. 1382.
[48] Vogelman B, Craig WA. Kinetics of antimicrobial activity. JPediatr 1986;108:83540.
[49] Hyatt JM, Mckinnon PS, Zimmer GS, Schentag JJ. Theimportance of pharmacokinetic/pharmacodynamicsurrogate markers to outcome. Focus on antibacterialagents. Clin Pharmacokinet 1995;28:14360.
[50] Moore RD, Lietman PS, Smith CR. Clinical response toaminoglycoside therapy: importance of the ratio of peakconcentration to minimal inhibitory concentration. J infectDis 1987;155:939.
[51] Marik PE. Aminoglycoside volumer of distribution andillness severity in clinically ill patients. Anesth intensiveCare 1993;21:1723.
[52] Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multipledaily doses of aminoglycosides: a meta-analysis. BMJ1996;312:33845.
[53] Lipman J, Scribante J, Gous AG, Hon H, Tshukutsoane S, TheBaragwanath Ciprofloxacin Study Group. Pharmacokineticsprofiles of high dose intravenous ciprofloxacin in severesepsis. Antimicrob Agents Chemother 1998;42:22359.
[54] Thomas JK, Forrest A, Bhavnani SM, Hyatt JM, Cheng A,Ballow CH, et al. Pharmacodynamics evaluation of factorassociated with the development of bacterial resistance inacutely ill patients during therapy. Antimicrob AgentsChemother 1998;42:5217.
[55] Schentag J. Pharmacokinetic and pharmacodynamicsurrogate markers: studies with fluoroquinolones inpatients. Am J Health-Syst Pharm 1999;56(Suppl. 3):S214.
[56] Craig WA. Pharmacokinetics/pharmacodynamicsparameters: rationale for antimicrobial dosing of men andmice. Clin Infect Dis 1998;26:112.
[57] Manduru M, Mihm LB, White RL, Friedrich LW, Flume RA,Bosso JA. In vitro pharmacodynamics of ceftazidime
against P. aeruginosa isolates from cystic fibrosis patients.Antimicrob Agents Chemother 1997;41:20536.
[58] Wysocki M, Delatour F, Faurisson F, Rauss A, Pean Y, MissetB, et al. Continuous versus intermittent infusion ofvancomycin in severe Staphylococcal infections:prospective multicenter randomised study. AntimicrobAgents Chemother 2001;45:24607.
[59] Garaffo R. Bases pharmacodynamiques de ladministrationIV des beta lactamines par perfusion continue:optimisation de lactiviteantibacterienne sur les bacilles agram negatif. Antibiotics 2002;4:227.
[60] Viaene E, Chanteux H, Servais H, Mingeot Leclerc MP,Tulkens P. Comparative stability of antipseudomonalagents administration through portable elastomeric pumps(home therapy for cystic fibrosis patients) and motor
operated syringes (intensive care units). Antimicrob AgentsChemother 2002;8:232732.
[61] Swanson D, De Angelis C, Smith I, Schentag J. Degradationkinetics of imipenem in normal saline and in humanserum. Antimicrob Agents Chemother 1986;5:9367.
[62] Scaglione F. Can PK/PD be used in everyday clinicalpractice. Int J Antimicrob Agents 2002;19:34953.
[63] Frimodt-Moller N. How predictive is PK/PD for antibacterialagents? Int J Antimicrob Agents 2002;19:3339.
[64] Carlet J, Tabah A. Antibiotherapie des etats infectieuxgraves. Med Mal Infect 2006;36:299303.
[65] Bolmstrom A. Determination of minimum bactericidalconcentrations, kill curves, and postantibiotic effects withthe E-test technology. Diagn Microbiol Infect Dis1994;19:18795.
[66] Griswold JA, Grube BJ, Engrav LH, Marvin JA, Heimbach DM.Determinants of donor sites infections in small burn grafts.
J Burn Care Rehabil 1989;10:5315.[67] Piel P, Scarnati S, Goldfarb W, Slater H. Antibiotics
prophylaxis in patients undergoing burn wound excision. JBurn Care Rehabil 1985;6:4224.
[68] Recommandations pour la pratique de lantibioprophylaxieen chirurgie. Ann Fr Anesth Reanim 1999;18:7585.
[69] Eagle H, Fleishman R, Levy M. Continuous vsdiscontinuous therapy with penicillin: the effect of theinterval between injections on therapeutic efficacy. N Engl JMed 1953;12:4818.
[70] Craig W, Ebert S. Continuous infusion of beta-lactamantibiotics. Antimicrob Agents Chemother 1992;36:257783.
[71] Mouton J, Vinks A. Is continuous infusion of beta lactam
antibiotics worthwhile? Efficacy and pharmacokinecticconsiderations. J Antimicrob Chemother 1996;38:515.
[72] Leder K, Turnidge J, Korman T, Grayson L. The clinicalefficacy of continuous infusion flucloxacillin in seriousstaphylococcal sepsis. J Antimicrob Chemother1999;43:1138.
[73] Roberts JA, Paratz J, Paratz E, Krueger WA, Lipman J.Continuous infusion of beta-lactam antibiotics in severeinfections: a review of its role. Int J Antimicrob Agents2007;30:118.
[74] Lode H, Borner K, Koeppe P. Pharmacodynamics offluoroquinolones. CID 1998;27:339.
[75] Garrelts JC, Jost G, Kowalsky SF, Krol GJ, Lettieri JT.Ciprofloxacin pharmacokinetics in burn patients.Antimicrob Agents Chemother 1996;40:11536.
b u r n s 3 7 ( 2 0 1 1 ) 1 6 2 6 25
-
8/11/2019 Antibiotics and the Burn Patient
11/11
[76] Johnson AP, Warren M, Livermore DM. Activity of linezolidagainst multi resistant Gram-positive bacteria from diversehospitals in the UK. J Antimicrob Chemother 2000;45:22530.
[77] Whitehouse T, Cepeda JA, Shulman R, Aarons L, Nalda-Molina R, Tobin C, et al. Pharmacokinetic studies oflinezolid and teicoplanin in the critically ill. J AntimicrobChemother 2005;55:33340.
[78] Adembri C, Fallani S, Cassetta MI, Arrigucci S, Ottaviano A,Pecile P, et al. Linezolidpharmacokineticpharmacodynamicprofile in critically ill septic patients: intermittent versuscontinuous infusion. Int J Antimicrob Agents 2008;31:1229.
[79] Lovering AM, Le Floch R, Hovsepian L, Stephanazzi J, Bret P,Birraux G, et al. Pharmacokinetic evaluation of linezolid inpatients with major thermal injuries. J AntimicrobChemother 2009 [Epub ahead of print].
b u r n s 3 7 ( 2 0 1 1 ) 1 6 2 626