RESEARCH
Prophylactic antibiotics for burns patients: systematic
review and meta-analysis
Tomer Avni, resident ,1 Ariela Levcovich, senior physician ,2 Dean D Ad-El, head of department,3 Leonard
Leibovici, head of department,1 Mical Paul, consultant4
ABSTRACT
Objective To assess the evidence for prophylactic
treatment with systemic antibiotics in burns patients.
Design Systematic review and meta-analysis of
randomised or quasi-randomised controlled trials
recruiting burns inpatients that compared antibiotic
prophylaxis (systemic, non-absorbable, or topical) with
placebo or no treatment.
Data sourcesPubMed, Cochrane Library, LILACS, Embase,
conference proceedings, and bibliographies. No
language, date, or publication status restrictions were
imposed.
Review methods Two reviewers independently extracted
data. The primary outcomewas all causemortality. Risk or
rate ratios with 95% confidence intervals were pooled
with a fixed effect model if no heterogeneity was present.
Results 17 trials were included. Trials that assessed
systemic antibiotic prophylaxis given for 4-14 days after
admission showed a significant reduction in all cause
mortality (risk ratio 0.54, 95% confidence interval 0.34 to
0.87, five trials). The corresponding number needed to
treat was 8 (5 to 33), with a control event rate of 26%.
Perioperative non-absorbable or topical antibiotics alone
did not significantly affect mortality. There was a
reduction in pneumonia with systemic prophylaxis and a
reduction in wound infections with perioperative
prophylaxis. Staphylococcus aureus infection or
colonisation was reduced with anti-staphylococcal
antibiotics. In three trials, resistance to the antibiotic
used for prophylaxis significantly increased (rate ratio
2.84, 1.38 to 5.83). The overall methodological quality of
the trials was poor.
Conclusions Prophylaxis with systemic antibiotics has a
beneficial effect in burns patients, but the
methodological quality of the data is weak. As such
prophylaxis is currently not recommended for patients
with severe burns other than perioperatively, there is a
need for randomised controlled trials to assess its use.
INTRODUCTION
Severe burns are an important health burden world-
wide and affect young healthy adults and children.12
Infections among burns patients are a major problem;
the reported incidence of nosocomial infections varies
at 63-240 per 100 patients and 53-93 per 1000 patient
days, depending mainly on the definitions used.3 4
Infections are independently associated with adverse
outcomes and mortality.3 4 In a series of 175 patients
with severe burns, infections precededmultiorgan dys-
function in 83% of patients and were considered as the
direct cause of death in 36% of patients who died.5
In burns patients infections arise from multiple
sources. Burn wounds become rapidly infected with
Gram positive bacteria, mainly staphylococci, that
are normal deep inhabitants of the sweat glands and
hair follicles exposed by the burn.6 Themoist, vascular
burn eschar further fosters microbial growth. Gram
negative bacterial infections result from translocation
from the colon because of reduced mesenteric blood
flow at the time of burn and subsequent insults.7
Furthermore, several immune deficits have been
described among burns patients, including impaired
cytotoxic T lymphocyte response,myeloidmaturation
arrest causing neutropenia, impaired neutrophil func-
tion, and decreased macrophage production.6 8-10
Finally, burns patients can incur hospital acquired
infections common to other patients in intensive care
units, including intravascular catheter related infec-
tions and ventilator associated pneumonia, with an
overall incidence of infection higher than that of
other patients in intensive care units.3 4
Antibiotic prophylaxis reduces mortality, bacterae-
mia, and ventilator associated pneumonia among
patients in intensive care units.11 12 Similarities between
intensive care and burns patients suggest possibly simi-
lar benefit of prophylaxis. Both populations are criti-
cally ill, andbacterial translocation from the colon is an
important source of infection, as are foreign bodies and
invasive procedures. In burns patients the skin is an
additional source of infection, and they have a higher
degree of immunosuppression. Nevertheless, there is a
broad and uniform consensus in the current literature
that prophylaxis with systemic antibiotics should not
be given to patients with severe burns. Recommenda-
tions for management do not address systemic anti-
biotic prophylaxis1 13 or explicitly state that
prophylactic antibiotics are not recommended.14-18
The rationale given is lack of evidence, no benefit, or
risk for adverse events, mainly colitis associated with
Clostridium difficile and induction of antibiotic
1Department of Medicine E, Rabin
Medical Center, Beilinson Hospital,
Sackler Faculty of Medicine, Tel-
Aviv University, Israel
2Department of Medicine B, Rabin
Medical Center, Beilinson Hospital
3Department of Plastic Surgery
and Burns, Rabin Medical Center,
Beilinson Hospital
4Unit of Infectious Diseases, Rabin
Medical Center, Beilinson Hospital
Correspondence to: M Paul
paulm@post.tau.ac.il
Cite this as: BMJ 2010;340:c241
doi:10.1136/bmj.c241
BMJ | ONLINE FIRST | bmj.com page 1 of 10

resistance. Indeed, most episodes of bloodstream
infection after the first week are caused by hospital-
type multidrug resistant bacteria.4 19 Recommenda-
tions regarding perioperative prophylaxis vary and
most sources recommend limited perioperative pro-
phylaxis only for those with severe burns (>40% total
body surface area).14 16 17
We performed a systematic review and meta-analy-
sis of randomised and quasi-randomised controlled
trials assessing antibiotic prophylaxis for burns
patients, both in the perioperative and general setting.
We primarily examined the effect of prophylaxis on all
cause mortality.
METHODS
Selection criteria
We included randomised controlled trials or quasi-ran-
domised trials (with inadequate allocation generation
methods), recruiting inpatientswith burns injuries (any
total body surface area or burn degree, with or without
inhalation injury), regardless of publication status or
language.The intervention assessedwas antibiotic pro-
phylaxis versus placebo or no treatment. Prophylaxis
was defined as antibiotics administered to patients
without documented infection regardless of systemic
inflammatory signs, including systemic antibiotics
given intravenously, orally, or intramuscularly; non-
absorbable oral antibiotics; or topical (wound dressing
or inhalation) antibiotics. Regimens including both
systemic and non-absorbable or topical antibiotics
were included in the systemic category. Antibiotics
could be administered at any time after admission
(“general”) or specifically targeted at a surgical proce-
dure (“perioperative”). We excluded topical non-anti-
biotic antimicrobial ointments or dressings (silver with
or without sulpha, iodine, or mafenide) and anti-
fungals, unless applied identically to intervention and
control arms. We excluded dose or schedule compar-
isons of the same antibiotics.
Outcomes
The protocol defined primary outcome was all cause
mortality 100 days after randomisation. None of the
studies reported 100 day data or similar, nor at another
fixed point in time, and so we extracted in hospital
mortality from all the studies, per protocol. Secondary
outcomes included bacteraemia, pneumonia (includ-
ing ventilator associated pneumonia), infection of the
burn wound, length of stay in hospital, infections
caused by Pseudomonas aeruginosa, Staphylococcus aureus,
and meticillin resistant S aureus (MRSA), resistance
induction, fungal infections (fungaemia or other clini-
cal fungal infection), and adverse events. Resistance
inductionwas defined per protocol as clinical infection
(not colonisation) caused by bacteria resistant to one or
more of the antibiotics included in the prophylactic
regimen. Studies, however, reported only on selected
“resistant isolates” (including both clinical and colonis-
ing bacteria); these data and their definitions were
extracted. Similarly, we accepted and documented
other outcomes definitions used in individual studies.
Search methods
We searched PubMed (1966 to February 2009),
Cochrane Library (issue 4, 2008), LILACS (1982 to
February 2009), Embase (1974 to October 2009), and
conference proceedings (Interscience Conference on
Antimicrobial Agents and Chemotherapy 1995-2008;
European Congress of Clinical Microbiology and
Infectious Diseases 2000-8; Annual Meeting of the
American Burn Association 2001-9; Congress of the
International Society for Burn Injuries 2007; and the
Annual Southern Region Burn Conference 2008-9).
We crossed the words “burn” or “total body surface
area or TBSA” and their MESH terms with the terms
“antibiotic,” “infection”, “sepsis”, or “bacteremia”. For
PubMed, this was combined with the Cochrane highly
sensitive filter for randomised controlled trials.20 We
scanned the references of all included articles for addi-
tional studies. Authors were contacted to complement
data on mortality and trial methods (one author21 sup-
plied additional data on methods).
Data collection
Two reviewers (TA and AL) independently inspected
each reference identified by the search, scanned full
texts of relevant studies, applied the inclusion criteria,
and extracted the data. Disagreements on data extra-
ction were resolved by discussion with a third reviewer
(MP). We assessed risk of bias in duplicate using
domain based evaluation, classifying studies primarily
according to the risk of non-random allocation of
patients to the intervention arm (sequence generation)
and concealment of this process (allocation conceal-
ment). These were graded as adequate, unclear, or not
described and inadequate (for example, alternation,
allocation by day of admission, hospital room), as
recommended in the Cochrane Handbook.20 We also
assessed blinding and intention to treat analysis. The
effect of allocation concealment on results was assessed
Publications identified by initial search (n= 368)
Potentially relevant publications (n=39)
Eligible randomised or quasi-randomised controlled trials (n=27)
Included randomised or quasi-randomised controlled trials (n=17)
Not relevant after abstract review (n=329)
Non-randomised (n=12):
Non-randomised comparative clinical studies (n=822-29)
Non-comparative clinical studies (n=430-33)
Additional randomised controlled trials
identified in reference search (n=5)
Excluded (n=15):
Non-antibiotic intervention (n=534-38)
Antibiotic v non-antibiotic intervention (n=339-41)
Antibiotic v other antibiotic (n=342-44)
Treatment, not prophylaxis (n=445-49)
Fig 1 | Identification of studies for inclusion
RESEARCH
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through sensitivity analysis, with restriction of the ana-
lysis to studies with adequate allocation concealment.
Data analysis
Dichotomous outcomes (mortality, resistance develop-
ment, and adverse events) are expressed per patient
and count data (infections, bacteraemia) are given per
patient day. Individual study results are expressed as
risk ratios or rate ratios, respectively, with 95% confi-
dence intervals. Rate ratios were calculated as the ratio
of events per patient day. Results were pooled with the
Mantel-Haenszel fixed effect model (Review Manager
(RevMan), version 5 for Windows, Cochrane
Collaboration, Oxford). We used χ2 test to determine
heterogeneity (P<0.1) or an I2 measure for inconsis-
tency (>50%).20 Outcomes with significant heterogene-
ity were not pooled. We anticipated heterogeneity
related to total body surface area and degree of burn
but did not perform subgroup analyses because of pau-
city of trials. Analyses were stratified by antibiotic
mode and intervention: systemic antibiotics (which
could be administered in the general or perioperative
setting), non-absorbable antibiotics, and topical anti-
biotics. Because of paucity of trials in each analysis,
we did not use any formal method to investigate pub-
lication bias.
Table 1 | Study characteristics of trials examining prophylactic antibiotics for burns patients in general settings. Figures are means (SD or SE) or median
(range) unless stated otherwise
Study and intervention details
Intervention
duration (days)
No of patients
randomised
Age
(years)
TBSA
(%)
3rd degree
burns (%)
Inhalation
injury (%)
Barret 200152
Non-absorbable per nasogastric tube polymyxin E,
tobramycin, amphotericin B Until open burn area
<10% TBSA
11 8 (1) 67 (6) 100 75
Placebo 12 9.4 (2) 58 (6) 100 63.6
De la Cal 200553
Systemic intravenous cefotaxime + oropharyngeal
paste and non-absorbable digestive administration
of polymyxin E, tobramycin, amphotericin B 4
58 41.4 (17.1) 34 (21.4) 19.3 (15.3) 64.2
Placebo 59 48.2 (28.5) 37.7 (21.1) 19.0 (18.8) 68.5
Desai 199154
Topical gentamicin 1% cream
Until wound healing
7 11.4 (1.2) 35 (7) 20 (9)
NS
No treatment 8 9.5 (1.6) 50 (6) 32 (7)
Deutsch 199055
Systemic and non-absorbable oral/nasogastric tube
erythromycin, neomycin, nystatin 10
15 44.7 (15-79) 49.9 (22-91) 26.3 (0-75) 26.7
No treatment 12 35 (18-75) 44.9 (20-75) 26.3 (0-50) 41.7
Durtschi 198256
Systemic intravenous or oral penicillin
5
25 31.1 (18-77) 14.9 (1-70)
NS NS
Placebo 26 36.8 (18-66) 20 (1-91)
Kimura 199857
Systemic per nasogastric tube sulfamethoxazole-
trimethoprim 10
21 44 (10-91) 49 (22-87)
NS
52
Placebo 19 48 (12-85) 43 (20-80) 63
Levine 197865
Inhalation gentamicin
10
12 28.1 53.8
NS
100
Placebo 18 34.3 57.6 100
Livingston 199021
Topical neomycin and bacitracin
Until graft healing
18 <20% TBSA 46 (22); 20-40%
27 (5); >40% 49 (10)
<20% TBSA 14 (5); 20-40%
29 (7); >40% 47 (6)
NS 22.2
Normal saline 15 <20% TBSA 43 (27); 20-40%
34 (20); >40% 43 (19)
<20% TBSA 11 (3); 20-40%
28 (6); >40% 53 (16)
NS 33.3
Lowbury 196858
Topical silver nitrate + gentamicin Until burns had healed
or were grafted
21
NS <30 NS NS
Topical silver nitrate 20
Munster 198959
Systemic intravenous polymyxin B*
7
22 34.4 29.3
NS NS
No treatment 23 38.8 32.8
Ugburo 200464
Systemic oral ampicillin + oxacillin
14
21 22.9 (4.1) 41.5 (5.8)
NS 0Systemic intravenous gentamicin+ oral erythromycin 20 24.9 (3.3) 46 (5.6)
None 20 23.3 (3) 44.3 (6.3)
TBSA=total body surface area; MRSA=meticillin resistant S aureus.
**Two sequential parts randomising patients to general systemic prophylaxis (first part) and perioperative systemic prophylaxis (second part), kept separate in our analyses.
RESEARCH
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RESULTS
The search yielded 368 different publications, of which
39were potentially relevant. Twenty seven studieswere
excluded (fig 1). We identified five trials through refer-
ence searching and altogether included 17 studies (37
trial arms), one of which was published as an
abstract.2150-65 The trials were published from 1968 to
2008 and recruited 1113 patients (median 51, range 15-
149). Four trials recruited children51525462 and the
others young adults (tables 1 and 2). The mean total
body surface area affected was >20% in 12 trials
(>30% in nine). Most trials did not report the number
of patients with full thickness burns. Twelve adminis-
tered systemic antibiotic prophylaxis; six trial arms
assessed general5355-575964 and six perioperative
prophylaxis.5059-63 Systemic antibiotics usually targeted
Gram positive bacteria and were given for a median of
8.5 days (range 4-14) in the general setting. Two trials
assessing systemic general prophylaxis and none of the
trials in the perioperative setting included a non-absorb-
able component. One trial assessed only non-absorb-
able prophylaxis,52 three trials topical antibiotic
treatment,215458 and one trial inhalation antibiotics,65
targeting mainly Gram negative bacteria.
Five and six trials, respectively, described adequate
sequence generation and allocation concealment. Both
were inadequate in three quasi-randomised trials that
used alternation or hospital number for sequence
generation5558 59 and were not described in all other
trials (table 3 and fig 2). Patients and carers were
blinded in seven trials (six assessing systemic prophy-
laxis). Results by intention to treat were reported in all
but two trials.
Primary outcome
Nine trials reported all cause, in hospital mortality
(fig 3). Systemic prophylaxis in the general setting
was associated with a significant reduction in all cause
mortality (risk ratio 0.54, 95% confidence interval 0.34
to 0.87, five trials, 272 patients), without significant het-
Table 2 | Study characteristics of trials examining systemic prophylactic antibiotics for burns patients in perioperative
settings. Figures are means (SD or SE) or median (range) unless stated otherwise
Study and intervention details
Intervention
duration (days)
No of patients
randomised
Age
(years)
TBSA
(%)
Third degree
burns (%)
Inhalation
injury (%)
Alexander 198251
Systemic intravenous cephalothin
1
127 10.5 (0.4)
NS NS NS
Placebo 122 10.8 (0.4)
Alexander 198450
Systemic antibiotics tailored to wound
cultures 1
35
NS
45.7%>30%
NS NS
No treatment 34 38.2%>30%
Munster 198959
Systemic intravenous polymyxin B*
5
6 47.7 54.8
NS NS
No treatment 11 40.6 38.4
Piel 198560
Systemic intravenous cephalosporin
1
25 33.6 42.6
NS NS
Placebo 26 39.2 37
Ramos 200861
Systemic intravenous cephalothin or
antibiotics tailored to surveillance cultures 2
46 39 (21.7) 21.6 (21)
NS NS
No treatment 44 35 (22) 27.7 (22.3)
Rodgers 199762
Systemic intravenous cefazolin
1
10 1.5 10
NS NS
Placebo 10 1.9 11
Steer 199763†
Systemic intravenous teicoplanin
1
67 (110 episodes) 38 (23-54) 8.5 (4-18) 44
NS
Placebo 67 (110 episodes) 42.5 (26-56) 8.0 (4-16) 45
TBSA=total body surface area; NS=not stated; MRSA=meticillin resistant S aureus.
*Two sequential parts randomising patients to general systemic prophylaxis (first part) and perioperative systemic prophylaxis (second part), kept
separate in our analyses.
†Trial included patients before surgery (46% of episodes) or change of dressing.
P
er
ce
n
ta
g
e
Ad
eq
ua
te
se
qu
en
ce
ge
ne
rat
ion
All
oc
ati
on
co
nc
ea
lm
en
t
Bl
ind
ing
Int
en
tio
n t
o t
rea
t
0
20
40
60
80
100
Yes (low risk of bias) Unclear No (high risk of bias)
Fig 2 | Assessment of overall risk of bias
RESEARCH
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Table 3 | Methods and outcome definitions used in individual trials
Study
Allocation
generation
Allocation
concealment Blinding*
Intention to
treat analysis
Secondary outcomes evaluated
and definitions
Resistance development/
surveillance cultures†
Alexander 198251 Adequate (random
choice of envelopes)
Adequate (central
pharmacist)
DB (placebo used, only
pharmacist aware of
treatment assignment)
Yes Wound infection (discharge of pus from
graft associated with graft loss); P
aeruginosa and S aureus infections;
hospital stay
NA. No surveillance
Alexander 198450 Unclear (not stated) Unclear (not stated) Open (treatment and
control patients placed in
different wards)
Yes Bacteraemia; wound infection NA. Wound and blood
surveillance
Barret 200152 Adequate (random
number chart)
Adequate (central
pharmacy)
DB (placebo used, only
pharmacist aware of
treatment assignment)
Yes Pneumonia (by CDC criteria or similar66);
systemic fungal infection; hospital stay
NA. Wound, sputum, urine,
blood, gastric aspirates,
and stool surveillance
De la Cal 200553 Unclear (not stated) Adequate (central,
pharmacy and kept in
sealed envelopes)
DB (placebo used, only
pharmacist aware of
treatment assignment) +
evaluator blinded
No Pneumonia and bacteraemia (CDC
criteria66); wound infection (according to
previously proposed criteria67);
candidaemia; P aeruginosa and S aureus
infections; hospital stay
Unrelated; ventilator
associated pneumonia or
bacteraemia caused by
MRSA. Wound, throat,
rectal surveillance
Desai 199154 Unclear (not stated) Unclear (not stated) Open Yes Wound infection (chondritis, defined);
hospital stay
Related; chondritis caused
by gentamicin-resistant
bacteria. Wound
surveillance
Deutch 199055 Inadequate
(chronological
alternation)
Inadequate
(chronological
alternation)
Open Yes formortality;
no for secondary
outcomes
Wound and fungal infection (positive
wound cultures); bacteraemia; P
aeruginosa and S aureus infections;
hospital stay
NA. Wound surveillance
Durtschi 198256 Unclear (not stated) Unclear (not stated) DB (placebo used) Yes Wound infection (sepsis and warm,
spreading, painful cutaneous erythema);
bacteraemia;Paeruginosa, Saureus, and
fungal infections; hospital stay
Unrelated; infections
caused by gentamicin-
resistant bacteria. Wound,
rectal surveillance
Kimura 199857 Unclear (not stated) Adequate (central
pharmacy)
DB Yes Pneumonia (by CDC criteria66); P
aeruginosa and S aureus infections
Unrelated; MRSA
infections. No surveillance
Levine 197865 Unclear (not stated) Unclear (not stated) Single or DB (placebo
inhalations used)
Yes Pneumonia (pulmonary infiltrate);
bacteraemia; P aeruginosa infections
NA. Blood surveillance
Livingston 199021 Adequate (cards
shuffled at
assignment)
Adequate (cards
placed in sealed
envelopes)
Open Yes Woundinfection (>10%graft lossand >105
organisms/g tissue, both innon-adherent
graft and recipient site; candida wound
infections; hospital stay
Unrelated; MRSA
infections. Wound
surveillance
Lowbury 196858 Inadequate
(alternation)
Inadequate
(alternation)
Open (no placebo, no
blinding described)
Yes P aeruginosa and S aureus infections Related; infections caused
by gentamicin-resistant
bacteria. Wound
surveillance
Munster 198959 Inadequate
(randomised by
hospital number)
Inadequate
(randomised by
hospital number)
Open (no placebo, no
blinding described)
Yes No secondary outcome NA. No surveillance
Piel 198560 Unclear (not stated) Unclear (not stated) Open(intervention listedon
bedside flow chart)
Yes Bacteraemia NA. Wound and blood
surveillance
Ramos 200861 Unclear (not stated) Adequate (sealed
envelopes)
Evaluator Yes Wound infection (graft loss with swelling,
erythema, increased temperature,
tenderness or purulent discharge)
NA. Wound surveillance
Rodgers 199762 Adequate (table of
random numbers)
Unclear (not stated) DB (placebo used, only
pharmacist and one un-
blinded investigator in the
operating room aware of
treatment assignment) +
evaluator
Yes Wound infection (clinical indication of
infection with positive quantitative skin,
wound biopsy, or blood cultures);
candida wound infection; bacteraemia; P
aeruginosa and S aureus infections
NA. Wound and blood
surveillance
Steer 199763 Unclear (not stated) Unclear (not stated) DB (placebo used,
teicoplanin colour masked,
only pharmacist aware of
treatment assignment)
Yes, but analysis
based on
episodes
Wound infection (biopsy and quantitative
tissue or skin cultures); pneumonia
(respiratory infection manifested by
sepsis and increase of purulent
tracheobronchial secretions or worsening
pulmonary gas exchange); P aeruginosa
and S aureus infections; bacteraemia;
candidaemia
Related and unrelated;
infections caused by
teicoplanin-resistant
staphylococci and MRSA.
Wound and blood
surveillance
Ugburo 200464 Adequate (table of
random numbers)
Unclear (not stated) Open Yes Wound infection (clinical infection using
previously proposed criteria 68, with
histological and microbiological
confirmation);P aeruginosa and S aureus
infections
NA. Wound surveillance
*DB=double blind; patient and carer were blinded to treatment; NA=not assessed.
†Resistance trait and types of infections reported and relation to study drugs (related: assessment of resistance to one or more of the study drugs; unrelated: assessment of a resistance
trait unrelated to the study antibiotics) and surveillance cultures reported.
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erogeneity (P=0.21, I2=32%). The corresponding num-
ber needed to treat was 8 (5 to 33), with a control event
rate of 26%. The antibiotics used included cefotaxime,
trimethoprim-sulfamethoxazole, penicillin, poly-
myxin B, and a combination of oral neomycin, ery-
thromycin, and nystatin. The exclusion of trials with
inadequate allocation concealment increased benefit
(0.42, 0.22 to 0.79, three trials). There were no signifi-
cant differences in mortality for perioperative non-
absorbable or topical antibiotic prophylaxis.
Secondary outcomes
Outcome definitions varied between the trials; table 4
summarises the results. Seven trials comprising 4835
patient days reported onbacteraemia.One trial admin-
istering perioperative teicoplanin prophylaxis showed
a highly significant reduction (rate ratio 0.26, 0.15 to
0.45), 63 while all other trials, including those of the gen-
eral setting, showed no significant differences, both
individually and pooled. Five trials reported on pneu-
monia (mainly ventilator associated) (103 events, 2624
patient days). Use of systemic antibiotics in the general
or perioperative setting showed a significant reduction
in pneumonia (0.55 (0.36 to 0.84), three trials). Eleven
trials reported on burn wound infection (not colonisa-
tion) (295 events, 7357 patient days). Perioperative sys-
temic antibiotic prophylaxis had an advantage of
borderline significance (0.72 (0.52 to 1.01), four trials),
while general systemic and topical antibiotics had no
effect.Most trials did not report on length of admission
to hospital in a manner that could be pooled.
Microbiological assessment showed that infection or
colonisation byP aeruginosawas not significantly differ-
ent, both in trials assessing antibiotics with andwithout
an anti-pseudomonal spectrum of coverage (1.06, 0.66
to 1.71, four trials; and 0.89, 0.62 to 1.28, seven trials,
respectively). S aureus infections significantly
decreased with anti-staphylococcal prophylaxis (0.58,
0.43 to 0.76, six trials), while the three trials assessing
an antibiotic without anti-staphylococcal coverage
showed an overall increase but with significant hetero-
geneity (I2=51%). Similarly, MRSA infections signifi-
cantly decreased when anti-MRSA prophylaxis was
used (0.36, 0.19 to 0.70, three trials). Fungal infections
were documented more often with antibiotic prophy-
laxis, but without a significant difference (1.58, 0.63 to
3.99, seven trials).
While most trials performed routine surveillance
cultures, at least of burn wounds (table 2), results per-
taining to induction of resistance were scarce (table 3).
Isolation of bacteria resistant to the study antibiotics
from any site was significantly higher in the inter-
vention arm (2.84, 1.38 to 5.83, three trials, one topical,
two systemic). Three trials reported on resistant infec-
tions unrelated to the intervention antibiotic (MRSAor
resistance to gentamicin), which was lower in the inter-
vention arm (0.42, 0.18 to 0.98).
Six trials addressed adverse events comparatively, of
which three reported no events.Adverse events requir-
ing discontinuation of antibiotic treatment were speci-
fied; these consisted of rash in two trials51 63 and
diarrhoea in one.55 There was higher rate of disconti-
nuation because of adverse eventswith treatment over-
all (4.97, 1.08 to 22.96). Pseudomembraneous colitis
was not reported.
DISCUSSION
The pooled evidence in our systematic review shows a
significant decrease in all causemortalitywith systemic
antibiotic prophylaxis for 4-14 days among patients
with burns (mostly severe), with a number needed to
treat of 8 (5 to 33). Systemic prophylaxiswas associated
with a reduced rate of pneumonia and, when adminis-
tered perioperatively, with a reduced rate of burn
wound infections. Resistance of bacteria to the anti-
biotic used for prophylaxis increased. Our findings
are based on a few small trials and in most randomisa-
tion methods were unclear or clearly inadequate.
These results stand in contrast with the current consen-
sus regarding antibiotic prophylaxis for patients with
severe burns.14-18
Comparison with studies conducted in intensive care units
More evidence on the effects of antibiotic prophylaxis
is available from studies on other critically ill patients
in intensive care units. In this setting prophylaxis with
non-absorbable or topical (oropharyngeal) antibiotics
aims to decontaminate the digestive tract of Gram
negative bacteria, S aureus, and candida. Most trials
assessing antibiotic prophylaxis in intensive care
Systemic antibiotic prophylaxis (general)
Munster 198959
Durtschi 198256
Deutsch 199055
Kimura 199857
De la Cal 200553
Total events
Test for heterogeneity: χ2=5.85, df=4, P=0.21, I2=32%
Test for overall effect: z=2.51, P=0.01
Systemic antibiotic prophylaxis (perioperative)
Steer 199763
Munster 198959
Alexander 198450
Total events
Test for heterogeneity: χ2=1.04, df=2, P=0.60, I2=0%
Test for overall effect: z=0.02, P=0.99
Non-absorbable antibiotic prophylaxis
Barret 200152
Test for heterogeneity: NA
Test for overall effect: z=0.68, P=0.50
Local antibiotic prophylaxis
Levine 197865
Test for heterogeneity: NA
Test for overall effect: z=0.86, P=0.39
0.26 (0.03 to 2.16)
0.26 (0.03 to 2.17)
1.24 (0.58 to 2.68)
0.52 (0.18 to 1.49)
0.41 (0.17 to 0.97)
0.54 (0.34 to 0.87)
0.50 (0.05 to 5.43)
0.61 (0.08 to 4.67)
1.62 (0.42 to 6.25)
1.01 (0.38 to 2.70)
2.18 (0.23 to 20.84)
0.75 (0.39 to 1.44)
10.8
10.8
17.1
20.3
41.0
100.0
27.9
29.6
42.5
100
100.0
100.0
0.01 0.1 1 10 100
Study
Favours
prophylaxis
Favours
control
Relative risk
(95% CI)
Relative risk
(95% CI)
Weight
(%)
1/ 22
1/ 25
8/ 15
4/ 21
6/ 53
20/ 136
1/ 110
1/ 6
5/ 35
7/ 151
2/ 11
6/ 12
Antibiotic
prophylaxis
4/ 23
4/ 26
6/ 14
7/ 19
15/ 54
36/ 136
2/ 110
3/ 11
3/ 34
8/ 155
1/ 12
12/ 18
Control
Fig 3 | All cause mortality in burns patients according to type of antibiotic prophylaxis
RESEARCH
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units, however, also used broad spectrum systemic
antibiotics for the first few days. The full (systemic
plus non-absorbable) selective digestive decontamina-
tion regimen achieves a larger reduction in mortality
(odds ratio 0.71, 0.61 to 0.82) than the non-absorbable
intervention alone (0.94, 0.71 to 1.24).11 69 Selective
decontamination regimens reducemainly Gram nega-
tive infections,70 and induction of resistance has not
been shown in trials conducted in low resistance
settings.12 In the trials that assessed burns patients, sys-
temic antibiotics alone were used in all the periopera-
tive trials and some of the general prophylaxis trials. A
recent trial, independently showing a reduction in
mortality and ventilator associated pneumonia, used
the full selective decontamination regimen.53S aureus
infections were reduced with prophylaxis in the perio-
perative setting. Considering similar risk factors for
intensive care and burns patients, the unique suscept-
ibility of burns patients to infections caused by skin
flora, and the available evidence, it seems that the
optimal regimen for prophylaxis among burns patients
would be a full selective decontamination regimen
including systemic and non-absorbable antibiotics.
Antibiotics targeting Gram positive bacteria might be
of added value perioperatively after discontinuation of
the systemic antibiotic.
Strengths and limitations of study
We included systemic, non-absorbable, and topical
antibiotics to inspect the effects of each separately
and to fully appraise their combined effect on resis-
tance induction. We included all types of burns,
although the question of prophylaxis applies mainly
to patients with severe burns. Most trials recruited
patients with burns over more than 20% of total body
surface area, and themortality rate of the control group
was 25% in trials that assessed general systemic pro-
phylaxis and 17% in all trials reporting on mortality
(fig 3). Thepaucity of trials precluded separate analyses
for patients with severe or full thickness burns only.
Table 4 | Secondary outcomes in burns patients according to antibiotic treatment
Outcome No of trials Rate ratio (95% CI)
Heterogeneity
χ
2 P value I2
Bacteraemia*
Systemic general 453 55 56 62 1.30 (0.91 to 1.85) 0.56 0%
Topical, inhalation 165 0.92 (0.39 to 2.16) — —
Wound infection
Systemic general 553 55 56 62 64 1.13 (0.82 to 1.55) 0.92 0%
Systemic perioperative 450 51 61 63 0.72 (0.52 to 1.01) 0.17 40%
Topical 221 54 1.49 (0.67 to 3.34) 0.83 0%
Pneumonia
Total systemic 3 0.55 (0.36 to 0.84) 0.28 21%
Systemic general 253 57 0.52 (0.33 to 0.83) 0.12 58%
Systemic perioperative 163 0.71 (0.23 to 2.23) — —
Non-absorbable 152 2.70 (0.11 to 66.10) — —
Topical, inhalation 165 1.00 (0.42 to 2.37) — —
P aeruginosa infections
Total 12 0.95 (0.71 to 1.27) 0.94 0%
With anti-pseudomonal activity 455 58 64 65 1.06 (0.66 to 1.71) 0.97 0%
Without anti-pseudomonal activity 751 53 56 57 62-64 0.89 (0.62 to 1.28) 0.61 0%
S aureus infections
With anti-staphylococcal activity 651 57 58 62-64 0.58 (0.43 to 0.76) 0.72 0%
Without anti-staphylococcal activity 353 55 56 1.70 (1.09 to 2.64) 0.13 51%
Fungal infection
Total 7 1.58 (0.63 to 3.99) 0.56 0%
Antibacterials and antifungals 352 53 55 1.26 (0.26 to 6.14) 0.49 0%
Antibacterials without antifungals 421 56 62 63 1.78 (0.56 to 5.59) 0.34 11%
Resistance development†
Resistance trait related to prophylaxis 353 54 63 2.15 (1.25 to 3.70) 0.50 0%
Resistance trait unrelated to prophylaxis 321 56 58 0.42 (0.18 to 0.98) 0.70 0%
Adverse events requiring discontinuation†
Total 3 4.97 (1.08 to 22.96) 0.41 0%
Systemic general 155 13.10 (0.65 to 265.42) — —
Systemic perioperative 251 63 2.99 (0.47 to 19.02) 0.32 0
*With systemic prophylaxis in perioperative setting, one trial63 showed highly significant advantage with prophylaxis (0.26, 0.15 to 0.45), while
other50 showed no difference (1.16, 0.79 to 1.70), thus this category was not pooled and nor was overall assessment of systemic antibiotic
prophylaxis.
†Risk ratios shown.
RESEARCH
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Included trials span a long period, starting before
1968 and the last published in 2008.During this period
advances in support and surgical treatment and
changes in antibiotic treatment and resistance have
occurred, limiting the validity of the pooled evidence.
Randomisation methods were inadequate (quasi-ran-
domisation) in three trials, and most others did not
report the methods used. Although exclusion of the
quasi-randomised trials did not reduce the effect on
mortality, results should be interpreted with caution.
Finally, although we performed a comprehensive
search, we cannot be sure that we did not miss unpub-
lished trials or older trials that were not labelled as ran-
domised. The paucity of trials in each category
precluded the assessment of publication bias.
Implications for practice
Infections are the leading cause of death in patients
with severe burns, even given contemporary resuscita-
tion protocols and surgical techniques.5 The onset of
infection is difficult to pinpoint because patients with
severe burns often present with systemic inflammatory
signs and shock. Inhalation injury masks the appear-
ance of pneumonia. This difficulty has been addressed
by the American Burn Association’s consensus defini-
tions for sepsis, designed specifically for burns
patients.71 Evenwith improveddefinitions, it is difficult
to ensure early appropriate antibiotic treatment for
these patients; thus the appeal of antibiotic prophy-
laxis. In hospitals, burn units have notoriously been
known as a source for outbreaks of multidrug resistant
bacteria. Historically the appearance of MRSA and
multidrug resistant Pseudomonas and Acinetobacter spe-
cies were linked to burn units72-74 and more recently
vancomycin resistant Enterococcus species and S aureus
.75 76 Thus, the fear of further induction of resistance
with antibiotic prophylaxis is real. Weighting a survi-
val benefit against possible harm to future patients
through cross infectionwith resistant strains is difficult.
Most clinicianswould probably opt for the individual’s
immediate gain. The reduction in mortality shown in
the current analysis, however, needs to be confirmed in
a larger contemporary trial.
Implications for further research
Future trials should assess a full selective decontamina-
tion regimen including systemic and non-absorbable
antibiotics. The duration of the systemic component
can probably be limited to the first four days, similar
to the regimen used in themost recent trial and in trials
in the intensive care unit.12 53 77 Limited perioperative
prophylaxis targeting Gram positive bacteria can be
considered. Optimal resuscitation protocols and local
care should be provided uniformly to both arms to
assess the added benefit of antibiotic prophylaxis to
current best practice.14-18 Special attention should be
drawn to infection control practices during the trial to
avoid cross infection between the trial arms. Contem-
porary methods used in multicentre trials should
ensure adequate sequence generation and allocation
concealment. Although randomised controlled trials
might not be the optimal platform to assess develop-
ment of resistance (randomisedpatients are in the same
unit and the timeframe is inadequate),78 special
attempts should be placed on documenting the effect
of prophylaxis on colonisation (using surveillance cul-
tures) and clinical infections caused bymultidrug resis-
tant bacteria. Other adverse effects including C difficile
colitis and fungal infections should be addressed. Ulti-
mately, however, a patient’s survival incorporates
both ill effects and the benefit of prophylaxis and is
the goal of managing burns patients. The current ana-
lysis (26%mortality in the control arm and relative risk
of 0.54) suggests that an individualmulticentre trial can
be powered to assess all cause mortality as the primary
outcome (about 200 patients per arm for a power of
80%). In hospital mortality among burns patients is
highly variable; a fixed point in time relevant to the
assessment of benefit and harm should be used.
In summary, we have shown a discrepancy between
current guidelines for management of burns patients
recommending against antibiotic prophylaxis and the
evidence showing a reduction of about 50% in all cause
mortality with systemic antibiotic prophylaxis. Given
the paucity and limitations of the available evidence,
this should serve mainly as an urgent call for a large
randomised controlled trial.
Contributors:MP was responsible for conception of the trial and is
guarantor. TA, AL, and MP wrote the protocol, carried out searches,
extracted and analysed the data, and wrote the manuscript. All authors
critically revised the manuscript.
Funding:This research received no specific grant from any funding agency
in the public, commercial, or not-for-profit sectors.
Competing interests: None declared.
Ethical approval: Not required.
Data sharing: Analyses in RevMan software are available from the
corresponding author at paulm@post.tau.ac.il.
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WHAT THIS STUDY ADDS
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Accepted: 24 November 2009
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