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Review
Centre des brules, Centre hospitalier St Joseph et St Luc, 20 quai Claude Bernard, 69007 Lyon, France
Centre des brules, Centre hospitalo-universitaire, Nantes, France
c
Centre des brules, Groupe hospitalier Cochin, Paris, France
d
Centre des brules, Hopital de la Conception, Marseille, France
e
Centre des brules, Hopital Edouard Herriot, Lyon, France
f
Centre des brules, Hopital dInstruction des Armees Percy, Clamart, France
g
Centre des brules, Hopital Pellegrin-Tripode, Bordeaux, France
b
article info
abstract
Article history:
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 Gramnegative organisms, the most effective molecules are 20 years old and there is little hope of
Keywords:
any new product available even in the distant future. Therefore, it is obvious that currently
Antibiotics
available antibiotics should not be misused. With this aim in mind, the following review was
Antibiotic therapy
conducted by a group of experts from the French Society for Burn Injuries (SFETB). It
Burn
examined key points addressing the management of antibiotics for burn patients: when
Burn patient
Bacterial resistance
Pharmacokinetics
these compounds. The authors also considered antibioprophylaxis and some other key
Pharmacodynamics
points such as: infection diagnosis criteria, bacterial inoculae and local treatment. French
Dosage
guidelines for the use of antibiotics in burn patients have been designed up from this work.
# 2009 Elsevier Ltd and ISBI. All rights reserved.
Contents
1.
2.
3.
4.
5.
General considerations . . . . . . . . . . . . . . . . . .
1.1. Introduction. . . . . . . . . . . . . . . . . . . . . .
1.2. Infection criteria . . . . . . . . . . . . . . . . . .
1.3. Dealing with local infection . . . . . . . . .
1.4. Role of bacterial population (inoculum)
Time for onset of antibiotic therapy . . . . . . . .
Bactericidal or bacteriostatic molecules? . . . .
Association or monotherapy? . . . . . . . . . . . . .
Adaptation of antibiotherapy . . . . . . . . . . . . .
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* 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).
0305-4179/$36.00 # 2009 Elsevier Ltd and ISBI. All rights reserved.
doi:10.1016/j.burns.2009.10.006
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17
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18
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6.
7.
8.
9.
10.
Duration of antibiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . .
Administration methods (dosage and rhythm of injection) . .
7.1. Notions of pharmacokinetics . . . . . . . . . . . . . . . . . . . .
7.2. Notions of pharmacodynamics . . . . . . . . . . . . . . . . . . .
7.3. Regimen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Monitoring antibiotic concentrations . . . . . . . . . . . . . . . . . . .
Perioperative antibiotic prophylaxis . . . . . . . . . . . . . . . . . . . .
Guidelines from the French Society for Burn Injuries (SFETB)
10.1. Guidelines for antibiotic therapy. . . . . . . . . . . . . . . . . .
10.2. Guidelines for antibiotics prophylaxis. . . . . . . . . . . . . .
10.3. Practical use. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.
General considerations
1.1.
Introduction
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1.2.
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19
19
19
19
19
19
20
20
20
20
21
24
Infection criteria
1.3.
1.4.
The probability of antibiotic-resistant mutant strains appearing within a bacterial population is not void. For example, with
Pseudomonas aeruginosa, the probability of a fluoroquinoloneresistant 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
106, the probability of a fluoroquinolone-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
18
2.
3.
4.
Association or monotherapy?
5.
Adaptation of antibiotherapy
19
7.3.
Regimen
6.
Duration of antibiotherapy
Excepted in few particular situations related to the microorganism 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 ventilator-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
7.2.
Notions of pharmacodynamics
8.
20
9.
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 Societe Francaise dEtude et de Traitement des
10.1.
10.2.
21
10.3.
Practical use
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 <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.
To the burns
- Presence of pus
- Rapid cleansing and detachment
- Appearance of blackish marks (necrosis or haemorrhage)
- Unexplained conversion of a lesion from superficial 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 find out the germ(s) involved.
More often, a simple swab is enough.
The biopsy is never systematic. It might be performed in
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 g 1 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
+
+
+
+
+
?
Bacterial infection
(1) Positive local signs:
Presence of a local or loco-regional inflammatory
reaction
Unfavourable and unexpected local evolution
22
Against Nosocomial Infections), the survey of the REAREACAT/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 recommandations pour la surveillance et la prevention des infections, BEH
June 1992) (100 guidelines for the monitoring and prevention of
infections).
In case of central venous catheter (CVC)-associated bacteraemia, 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 ml 1 of the same germ in quantitative culture of
the catheter
- Differential blood cultures with CVC/periph 5 or positivity time period CVC/periph 2 h to the same germ.
Lung infection
Pneumonia
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 temperature 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., Micrococcus 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.
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/imipenemcilastatin).
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
the MIC.
or 45 times
or 45 times
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 (specifically ticarcillin-R P. aeruginosa), the
targeted steady-state concentration is 3240 mg l 1 or 810 times MIC
23
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 (specifically 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 products 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 daily
1020 mg kg 1 per injection (total dose 3080 mg kg 1 daily)
Infuse for 30 min. Sample for Cmax immediately at the end of the
injection (due to the very quick diffusion time of the molecule)
Target (Cmax): >30 mg l 1 (optimal = 40 mg l 1) or >10 times the
MIC
Beware of occult water administration (0.5 ml per mg ciprofloxacin)
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
24
Oxazolidinones
[17]
a
Linezolide
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
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26