antibiotics and the burn patient

8/11/2019 Antibiotics and the Burn Patient

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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
mailto:[email protected]://dx.doi.org/10.1016/j.burns.2009.10.006http://dx.doi.org/10.1016/j.burns.2009.10.006mailto:[email protected]


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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



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


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


MIC

Ceftazidime

Continuous infusion

100150 mg kg1 daily


Administration in soft bags with volumetric pump is preferred due

to the risk of gas release, but continuous administration with electric

syringe is possible


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


Stability: 3 h 30 min at 25 8C


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/


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


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].

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