Antibiotic Concrane[1]

Antibiotic prophylaxis to reduce respiratory tract infections
and mortality in adults receiving intensive care (Review)
Liberati A, D’Amico R, Pifferi S, Torri V, Brazzi L
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2009, Issue 1
http://www.thecochranelibrary.com
Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Analysis 1.1. Comparison 1 topical plus systemic vs no prophylaxis, Outcome 1 overall mortality. . . . . . . . 54
Analysis 1.2. Comparison 1 topical plus systemic vs no prophylaxis, Outcome 2 mortality according to randomisation. 55
Analysis 1.3. Comparison 1 topical plus systemic vs no prophylaxis, Outcome 3 mortality according to blinding of the
studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Analysis 1.4. Comparison 1 topical plus systemic vs no prophylaxis, Outcome 4 RTIs. . . . . . . . . . . . 60
Analysis 1.5. Comparison 1 topical plus systemic vs no prophylaxis, Outcome 5 RTIs according to randomisation. . 61
Analysis 1.6. Comparison 1 topical plus systemic vs no prophylaxis, Outcome 6 RTIs according to blinding of the studies. 64
Analysis 2.1. Comparison 2 topical vs control, Outcome 1 overall mortality. . . . . . . . . . . . . . . 66
Analysis 2.2. Comparison 2 topical vs control, Outcome 2 mortality according to randomisation. . . . . . . . 70
Analysis 2.3. Comparison 2 topical vs control, Outcome 3 mortality according to blinding of the studies. . . . . 73
Analysis 2.4. Comparison 2 topical vs control, Outcome 4 RTIs. . . . . . . . . . . . . . . . . . . 75
Analysis 2.5. Comparison 2 topical vs control, Outcome 5 RTIs according to randomisation. . . . . . . . . 79
Analysis 2.6. Comparison 2 topical vs control, Outcome 6 RTIs according to blinding of the studies. . . . . . . 82
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care (Review) i
[Intervention Review]
Antibiotic prophylaxis to reduce respiratory tract infections

and mortality in adults receiving intensive care
Alessandro Liberati1 , Roberto D’Amico2 , Silvia Pifferi3 , Valter Torri4 , Luca Brazzi5
1 ItalianCochrane Centre, Mario Negri Institute, Milano, Italy. 2 Department of Oncology and Hematology, University of Modena
and Reggio Emilia, Modena, Italy. 3 Policlinico San Matteo, Pavia, Milano, Italy. 4 Laboratorio di Epidemiologia Clinica, Mario Negri
Institute, Milano, Italy. 5 IRCCS - Istituto di Anestesia e Rianimazione, Ospedale Maggiore Policlinico, Milano, Italy
Contact address: Alessandro Liberati, Italian Cochrane Centre, Mario Negri Institute, Via La Masa, 19, Milano, 20156, Italy.
[email protected]. (Editorial group: Cochrane Acute Respiratory Infections Group.)
Cochrane Database of Systematic Reviews, Issue 1, 2009 (Status in this issue: Unchanged)
DOI: 10.1002/14651858.CD000022.pub2
This version first published online: 26 January 2004 in Issue 1, 2004.
Last assessed as up-to-date: 25 November 2003. (Help document - Dates and Statuses explained)
This record should be cited as: Liberati A, D’Amico R, Pifferi S, Torri V, Brazzi L. Antibiotic prophylaxis to reduce respiratory tract
infections and mortality in adults receiving intensive care. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD000022.
DOI: 10.1002/14651858.CD000022.pub2.
ABSTRACT
Background
Pneumonia is an important cause of mortality in intensive care units. The incidence of pneumonia in such patients ranges between 7%
and 40%, and the crude mortality from ventilator associated pneumonia may exceed 50%. Although not all deaths in patients with
this form of pneumonia are directly attributable to pneumonia, it has been shown to contribute to mortality in intensive care units
independently of other factors that are also strongly associated with such deaths.
Objectives
The objective of this review was to assess the effects of antibiotics for preventing respiratory tract infections and overall mortality in
adults receiving intensive care.
Search strategy
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 3, 2003), which contains the Acute Respiratory
Infections (ARI) Group specialised trials register; MEDLINE (January 1966 to September 2003); EMBASE (January 1990 to September
2003); proceedings of scientific meetings and reference lists of articles from January 1984 to December 2002. We also contacted
investigators in the field.
Selection criteria
Randomised trials of antibiotic prophylaxis for respiratory tract infections and deaths among adult intensive care unit patients.
Data collection and analysis
At least two reviewers independently extracted data and assessed trial quality.
Main results
Overall 36 trials involving 6922 people were included. There was variation in the antibiotics used, patient characteristics and risk of
respiratory tract infections and mortality in the control groups. In 17 trials (involving 4295 patients) that tested a combination of
Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care (Review) 1
topical and systemic antibiotic, the average rates of respiratory tract infections and deaths in the control group were 36% and 29%
respectively. There was a significant reduction of both respiratory tract infections (odds ratio 0.35, 95% confidence interval 0.29 to
0.41) and total mortality (odds ratio 0.78, 95% confidence interval 0.68 to 0.89) in the treated group. On average 5 patients needed
to be treated to prevent one infection and 21 patients to prevent one death. In 17 trials (involving 2664 patients) that tested topical
antimicrobials alone (or comparing topical plus systemic versus systemic alone) the rates of respiratory tract infections and deaths in
the control groups were 30% and 26% respectively. There was a significant reduction of respiratory tract infections (odds ratio 0.52,
95% confidence interval 0.43 to 0.63) but not in total mortality (odds ratio 0.97, 95% confidence interval 0.81 to 1.16) in the treated
group.
Authors’ conclusions
A combination of topical and systemic prophylactic antibiotics reduces respiratory tract infections and overall mortality in adult patients
receiving intensive care. A treatment based on the use of topical prophylaxis alone reduces respiratory infections but not mortality. The
risk of occurrence of resistance as a negative consequence of antibiotic use was appropriately explored only in the most recent trial by
de Jonge which did not show any such effect.
PLAIN LANGUAGE SUMMARY

Antibiotics can help reduce mortality and respiratory infections in people receiving intensive care in hospital
People who need ventilation (mechanical breathing support) in intensive care can develop respiratory tract infections or pneumonia
(a lung infection). Some people will die because of these infections. The review of trials found that a combination of antibiotics that
are topical (where a drug is applied directly to the part being treated) and systemic (affecting the whole body) reduces mortality and
infections. The use of topical antibiotics alone will reduce the person’s infection but not influence their survival.
BACKGROUND Mortality: OR 0.90, 95% CI 0.79 - 1.04
RTIs: OR 0.37, 95% CI 0.31 - 0.43
Heyland 1994 (number of studies = 24, number of patients =
Description of the condition
3312)
Nosocomial infections, especially pneumonia, are an important Mortality: Relative Risk (RR) 0.87, 95% CI 0.79 - 0.97
cause of morbidity and mortality in intensive care units (ICU). RTIs: RR 0.46, 95% CI 0.39 - 0.56
The incidence of pneumonia has been reported to vary from 7% Kollef 1994 (number of studies = 16, number of patients = 2270)
to more than 40% in ICU patients. The crude mortality rate for Mortality: Risk Difference (RD) 0.019, 95% CI - 0.016 to 0.054
patients with ventilator-associated pneumonia (VAP) may exceed Pneumonia: RD 0.145, 95% CI 0.116 to 0.174
50%. Although not all deaths in patients with pneumonia are di- Tracheobronchitis: RD 0.052, 95% CI 0.017 to 0.087
rectly attributable to pneumonia, it has been shown to contribute
to ICU mortality independently of other factors that are also Hurley 1995 (number of studies = 26, number of patients = 3768)
strongly associated with deaths of these patients (Fagon 1996). In a Mortality: OR 0.86, 95% CI 0.74 - 0.99
case-controlled study an increase in mortality of 27% attributable RTIs: OR 0.35, 95% CI 0.30 - 0.42
to pneumonia was evidenced in ventilated patients (Fagon 1996). D’Amico 1998 (number of studies = 33, number of patients =
5727)
Description of the intervention Topical plus systemic (16 trials 3361 patients):
mortality: OR 0.80, 95% CI (0.69 to 0.93)
Considerable efforts have been made to evaluate methods for re- RTIs: OR 0.35, 95% CI (0.29 to 0.41)
ducing respiratory infection. One strategy involves the use of se- Topical alone (17 trials 2366 patients)
lective decontamination of the digestive tract (SDD). Different mortality: OR 1.01, 95% CI (0.84 to 1.22)
SDD protocols have been used in different trials and investigators RTIs: OR 0.56, 95% CI (0.46 to 0.68)
often disagree on what is the most appropriate definition of SDD. Nathens 1999 (number of studies = 21, number of patients = not
Traditionally SDD indicates a method designed to prevent infec- reported)
tion by eradicating and preventing carriage of aerobic potentially Mortality in surgical patients: OR 0.7, 95% CI 0.52 to 0.93
pathogenic micro-organisms from the oropharynx, stomach and Mortality in medical patients: OR 0.91, 95% CI 0.71 to 1.18
gut. It consists of antimicrobials applied topically to the orophar- All confirmed a statistically significant reduction in RTIs, though
ynx and through a naso-gastric tube. In some trials systemic an- the magnitude of the treatment effect varied from one review to
tibiotic therapy has been added in the first days after patients’ ad- another probably due to different number of studies and inclusion
mission to prevent ’early’ infections. criteria among them. The estimated impact on overall mortality
was less evident until the 1998 review (D’Amico 1998) but the
How the intervention might work interpretation of these equivocal results could be better understood
if one realises that between two and 3,000 patients are needed to
An SDD protocol based on oral non-absorbable antibiotics was
reliably detect a clinically relevant reduction in mortality (SDD
first used in 1984 by Stoutenbeek (Stoutenbeek 1994) in a group
Group 1993).
of multiple trauma patients. The incidence of nosocomial infec-
tion was reduced from 81% to 16% in a non-randomised com-
parison with an historical control group. Further studies tested the Why it is important to do this review
efficacy of SDD in ICU patients, with infection-related morbid- This paper is an updated version of the Cochrane review pub-
ity as the main endpoint. The results showed that SDD reduced lished in previous issues of The Cochrane Library including trials
infection but it was not clear whether there was a reduction in published up to September 2003.
mortality. Between 1991 and 1999 seven different meta-analyses (
Vanderbrouk-Gra 1991; SDD Group 1993; Heyland 1994; Kollef
1994; Hurley 1995, D’Amico 1998; Nathens 1999) on the effect
of SDD on respiratory tract infections (RTIs) and mortality were OBJECTIVES
published. Their results are summarised below:
To determine whether antibiotic prophylaxis reduces RTIs and
Vanderbrouk-Gra 1991 (number of studies = six, number of pa-
overall mortality in adult patients treated in ICUs.
tients = 491)
Mortality: Odds Ratio (OR) 0.70, 95% Confidence Interval (CI) Specifically, the main question left unanswered by existing ran-
0.45 - 1.09 domised controlled trials (RCTs) and previous meta-analyses was
RTIs: OR 0.12, 95% CI 0.08 - 0.19 whether different forms of antibiotic prophylaxis (i.e. the one test-
SDD Group 1993 (number of studies = 22, number of patients = ing topical antimicrobials or the one using a combination of topi-
4142) cal and systemic drugs) are effective in reducing overall mortality.
METHODS Search methods for identification of studies
Criteria for considering studies for this review Electronic searches
Types of studies We searched the Cochrane Central Register of Controlled Trials

(CENTRAL) which also includes the Cochrane Acute Respira-
All RCTs, published and unpublished, without language restric- tory Infection Group’s Specialized Register (The Cochrane Library,
tion, and testing the effect of antibiotic prophylaxis for the pre- 2003, issue 3); MEDLINE (January 1966 to September 2003);
vention of RTIs and deaths in adult ICU patients were considered. and EMBASE (January 1990 to September 2003) using similar
Only randomised trials (RCTs) were accepted because otherwise terms for the two databases, using the following search strategy:
control of selection bias could not be guaranteed; studies found - 1 exp Intensive Care Units/
upon closer scrutiny - not to be randomised were not included. 2 (intensive care unit$ or ICU).mp.
Types of participants 3 exp Critical Care/
Unselected adult general patients admitted to an ICU. Studies 4 Critical Care.mp.
based on specific pre-selected types of patients (i.e. patients un- 5 exp Critical Illness/
dergoing elective oesophageal resection, cardiac or gastric surgery, 6 Critical Illness.mp.
liver transplant or suffering from acute liver failure) were not in- 7 exp Ventilators, Mechanical/
cluded. Studies where the majority of patients (> 50%) did not 8 ventilator-associated pneumonia.mp.
undergo mechanical ventilation for more than 48 hours were also 9 or/1-8
excluded. The characteristics of excluded studies are reported in 10 exp Antibiotic Prophylaxis/
the table. 11 (antibiotic$ adj3 prophyl$).mp.
Types of interventions 12 exp Antibiotics, Combined/
13 or/10-12
Available RCTs have been grouped into two categories defined
14 exp Respiratory Tract Infections/
according to the type of antibiotic prophylaxis:
15 Respiratory Tract Infection$.mp.
a) studies where a combination of systemic and topical antibiotics
16 or/14-15
was tested against no prophylactic treatment (thereafter referred
17 9 and 13 and 16
as ’topical plus systemic versus no prophylaxis’);
18 exp Respiratory Tract Infections/pc [Prevention & Control]
b) studies where the experimental treatment tested was a topical
19 18 and 9
preparation (thereafter referred as ’topical versus control’). In this
20 17 or 19
latter category two subgroups of RCTs have been lumped, i.e.
21 RANDOMIZED CONTROLLED TRIAL.pt.
those where topical antibiotics were tested against an untreated
22 CONTROLLED CLINICAL TRIAL.pt.
control group and those where the combination of topical plus
23 RANDOMIZED CONTROLLED TRIALS.sh.
systemic drugs was compared with a protocol based on a systemic
24 RANDOM ALLOCATION.sh.
antimicrobial only.
25 DOUBLE BLIND METHOD.sh.
Any topical or systemic antimicrobial combination (that is: type
26 SINGLE-BLIND METHOD.sh.
of drugs) was accepted, because there were not data to assume a
27 or/21-26
difference in effect among the considered prophylactic treatments.
28 (ANIMAL not HUMAN).sh.
This obviously does not mean that all topical regimens and all sys-
29 27 not 28
temic regimens are truly equivalent but simply reflects our prag-
30 CLINICAL TRIAL.pt.
matic working assumption.
31 exp Clinical Trials/
Types of outcome measures 32 (clin$ adj25 trial$).ti,ab.
Two main outcomes were considered: RTIs and overall mortality. 33 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or
No restriction was made on the type of RTIs considered, and on mask$)).ti,ab.
RTIs diagnostic criteria chosen by the trialists. Both tracheobron- 34 PLACEBOS.sh.
chitis and pneumonia were acceptable. Pragmatically both primary 35 placebo$.ti,ab.
(diagnosed within 48 hours from admission) and acquired (diag- 36 random$.ti,ab.
nosed after 48 hours from admission) infections were considered, 37 or/30-36
even though we used data on acquired infections (i.e. the most 38 37 not 28
appropriate outcome to assess treatment effect) when both pieces 39 29 or 38
of information were available. Mortality was evaluated at hospital 40 20 and 39
discharge if this information was provided; otherwise mortality in
Searching other resources
ICU was used.
Other studies listed in previous meta-analyses were evaluated. No patients) compared topical treatment to no treatment or placebo,
formal inquiry was made through pharmaceutical companies. and six trials (totaling 1056 patients) compared topical and sys-
temic antibiotic treatment versus systemic antibiotic only.
Data collection and analysis We included two studies (Gaussorgues 1991; Laggner 1994)
among the ’topical SDD plus systemic antibiotic versus systemic
It has been documented in a qualitative review of published studies antibiotic’ group even if their design did not foresee explicitly the
(Brazzi 1992) that in many published trials some patients had use of systemic antibiotics because all patients in both arms were
been excluded from the final analysis. To overcome this limitation treated with systemic antibiotics on admission. Similarly, we in-
and be able to perform an “intention to treat analysis” we sought cluded the Jacobs (Jacobs 1992) study among the ’topical SDD
additional information from individual investigators of the trials plus systemic antibiotics versus control’ group because more than
included in the version of this review published in 1998 (D’Amico 90% of patients received a systemic antibiotic on admission.
1998); here we obtained data for an intention to treat analysis The four studies with a three arms comparison have been analysed
in 25/33 studies. For trials published after 1998 and included in as follows. In one study (Aerdts 1991) the two control groups were
this updated review (three studies) we relied only on published pooled together and compared to the treatment group. In two
information. Therefore data presented below are based on “an other studies (Lingnau 1997; Verwaest 1997) we split the study
intention to treat analysis” in a total of 25/36 studies. into two comparisons in which two different treatment arms were
Crude proportions of RTIs and mortality were our main treatment compared to the same control arm. In one study (Palomar 1997)
end-points. In addition to odds ratios of each outcome in each one of the two control arms was excluded because it received only
trial, computed with the fixed effects model, we computed the sucralfate.
number of ICU patients who need to be treated in order to prevent Overall, the total number of patients randomised to either an-
one infection and one death. The calculation was based on the tibiotic prophylaxis vs placebo or no treatment available for this
median rates of RTIs and deaths in untreated controls and the review is 6922. Final meta-analysis was based upon 36 trials with
common odds ratio for all trials. 38 comparisons.
Two pre-specified subgroup analyses based on quality criteria were A few studies (Gaussorgues 1991; Cerra 1992; Lenhart 1994)
carried out within the two main groups of RCTs above specified: could not contribute to the RTIs analysis as they reported the
-Quality of randomisation procedures (’Adequate’ versus ’Inade- number of episodes of RTIs and not the number of infected pa-
quate’) tients leaving 32 trials (totaling 5185 patients) for the final analy-
-Blinding of patients and doctors to allocated treatment (’Double- sis. Moreover, one trial (de Jonge 2003 ) did not assess RTIs as an
blind’ versus ’Open’). endpoint.
Mortality was evaluated in ICU in 24 trials (3597 patients); hos-
pital mortality was available only for nine RCTs (2810 patients),
the exact time of assessment of mortality was not determined in
RESULTS three trials (Jacobs 1992; Pneumatikos 2002; Lenhart 1994).
Most RCTs included general ICU patients. A few trials included
only trauma (Boland 1991; Georges 1994; Stoutenbeek 1994 (un-
Description of studies
published); Quinio 1995; Lingnau 1997); (Pneumatikos 2002) or
See: Characteristics of included studies; Characteristics of excluded surgical patients (Cerra 1992).
studies; Characteristics of ongoing studies. All patients were mechanically ventilated in 27 studies, the per-
Results of the search centage of ventilated patients was lower in six trials (Brun-Buisson
1989; Ulrich 1989; Blair 1991; Cockerill 1992; Winter 1992, de
Fifty-three potentially eligible RCTs were identified: 17 were ex-
Jonge 2003 ) and unknown in three (Finch 1991; Cerra 1992;
cluded (see table) (Hunefeld 1989; Flaherty 1990; Tetteroo 1990;
Lenhart 1994). In Brun-Buisson’s study the percentage of venti-
Martinez-Pellus 1993; Bion 1994; Lipman 1994; Martinez 1994;
lated patients was very low (59%) probably because the setting
Schardey 1994; Luiten 1995; Rolando 1996; Barret 2001; Nardi
of the study included both ’acute’ and ’intermediate’ areas of a
2001; Bouter 2002; Garbino 2002; Hellinger 2002; Rayes 2002;
medical ICU.
Zwaveling 2002) and one study (Anonymous 2003) could not be
The percentage of immunocompromised patients was usually
included as it is still unpublished and data in suitable form had
lower than 10%; it was higher only in five trials (Brun-Buisson
not been obtained at the time of this update.
1989; Finch 1991; Gastinne 1992; Jacobs 1992b; Laggner 1994).
Thirty-six RCTs were finally included in this review: 34 were pub-
Sucralfate was routinely used in all patients for stress ulcer pro-
lished (30 as full reports and four in abstract form) and two un-
phylaxis in nine trials (Gaussorgues 1991; Ferrer 1992; Jacobs
published (Stoutenbeek 1984; Lenhart 1994). Seventeen RCTs
1992; Laggner 1994; Lenhart 1994; Quinio 1995; Abele-Horn
(totaling 4295 patients) compared topical and systemic antibiotic
1997; Verwaest 1997; Bergmans 2001). In many RCTs only res-
treatment versus no treatment or placebo, 13 RCTs (totaling 1597
piratory tract infections (RTIs) acquired in ICU (i.e. diagnosed 0.63). The effect was stronger in RCTs where topical antimicro-
after 48 hours from admission) have been considered. Data on bials were tested against no prophylaxis (OR = 0.37, 95% CI =
primary and acquired infections are considered together only in 0.29 - 0.48). Less extreme results were observed in trials testing the
three trials (Boland 1991 and the two studies by Stoutenbeek combination of topical and systemic antibiotic against systemic
1984). Most studies (24 RCTs) evaluated only the occurrence of prophylaxis (OR = 0.81, 95% CI = 0.61 - 1.08).
pneumonia while seven RCTs evaluated tracheobronchitis too; in- These results indicate that five (95% CI = 4 - 5) or eight (95%
formation was lacking in one RCT. Diagnostic criteria differed CI = 6 - 11) patients need to be treated to prevent one infec-
across trials. Few authors provide quantitative details on the cut- tion depending on whether a combination of topical and systemic
off point used as positive bacteriological confirmation. Eight RCTs treatment or topical antimicrobials were tested (assuming, as base-
required a bacteriological confirmation obtained through a pro- line risk, the median values of 44% and 32%, respectively, among
tected catheter brush or a BAL (Broncho-Alveolar Lavage) to make control patients). Pre-defined subgroup analyses did not show a
diagnosis of pneumonia; 14 trials established that a positive tra- statistically significant effect on the estimates of treatment effect
cheal aspirate was adequate; nine RCTs established that no bac- by quality of randomisation and blinding status of the RCTs.
teriological confirmation was required to make diagnosis of RTIs
and in one trial the information was not available. Mortality
Overall, 36 RCTs including 6922 patients were available for the
Risk of bias in included studies mortality analysis. The mortality was 24% among treated patients
and 29 % among controls on RCTs using a combination of topical
Study quality was assessed looking at two criteria: plus systemic antibiotic; while it was 26% in both groups in RCTs
a) methods of randomisation (’Adequate’ versus ’Inadequate’); testing the effectiveness of topical SDD. The odds ratio was lower
b) use of blinding techniques (’Double blind’ vs ’Open’ studies). than unity in 26/38 comparisons but reached conventional statis-
The randomisation procedure was defined ’Adequate’ when it was tical significance in two RCTs (Lenhart 1994; de Jonge 2003); no
done by telephone through a pharmacy or a central office (eight trial showed a significant harmful effect of antibiotic prophylaxis.
RCTs) or using sealed envelopes (16 RCTs). It was defined ’In- Results indicate a statistically significant reduction in mortality
adequate’ when it was done using a computer generated list (six attributable to the use of a combination of topical and systemic
RCTs) or when patients were allocated by odd-even number (four treatment (OR = 0.78, 95% CI = 0.68 - 0.89). This suggests that
RCTs). Two RCTs (Lenhart 1994; Pneumatikos 2002) - where the 21 patients (95% CI = 14 - 43) (assuming a baseline risk of 29%,
information on randomisation procedure was not available - were median among control patients) need to be treated to prevent
included by default into the ’inadequate’ category. Randomisation one death. On the other hand, no treatment effect emerged when
was therefore classified as ’Adequate’ in 23 RCTs (4672 patients) RCTs testing topical antimicrobials were analysed (OR = 0.97;
and ’Inadequate’ in 12 (2050 patients). Eighteen RCTs adopted 95% CI = 0.81 - 1.16).
a ’double blind’ (3942 patients) and 18 an ’Open’ design (3706 The subgroup analyses produced the following results. Quality of
patients). These two quality criteria will be used to perform one- randomisation: Adequate (OR = 0.80, 95% CI = 0.69 - 0.92),
way subgroup analyses for two treatment comparisons (topical Inadequate (OR = 0.68, 95% CI = 0.48 - 0.97). Blind design:
plus systemic vs no treatment and topical alone vs no treatment) Double blind (OR = 0.63, 95% CI = 0.48 - 0.83), Open (OR =
on the two main outcomes (RTIs and overall mortality). 0.84, 95% CI = 0.71 - 0.98).
Effects of interventions
Respiratory tract infection
DISCUSSION
Results from 32 RCTs including 5185 patients were available for
the analysis of the effects of different types of antibiotic prophylaxis Ever since its introduction as an infection prevention method in
on RTIs. The frequency of RTIs was 16% among treated patients critically ill patients antibiotic prophylaxis based on SDD has re-
and 36% among controls in RCTs using a combination of topical mained controversial (Stoutenbeek 1994). Lack of standard pro-
plus systemic antibiotic and 17% and 30%, respectively, in RCTs tocol and insufficient numbers of patients have made it difficult to
testing the effectiveness of topical prophylaxis. Overall, the odds derive meaningful conclusions from individual clinical trials. Af-
ratio was lower than unity in all but two trials (Wiener 1995; ter an initial enthusiasm following results from early uncontrolled
Lingnau 1997) and reached conventional statistical significance (p studies and initial RCTs, antibiotic prophylaxis does not seem to
< 0.05) in 23/34 comparisons. be widely used as routine treatment in ICUs. The concern about
Results indicate a strong protective effect in RCTs where the com- the risk of long term emergence of antimicrobial resistance and
bination of topical and systemic treatment (OR = 0.35, 95% CI increased costs dominates in the most important documents on
= 0.29 - 0.41) was tested. A significant protection emerged when prevention of infections. A conservative attitude in introducing a
topical prophylaxis was considered (OR = 0.52 95% CI = 0.43 - new treatment into practice is understandable as long as doubts
on its efficacy exist. In fact studies on prevention of ventilator-as- decision was made a priori independently of the knowledge of
sociated pneumonia in ICU patients are very complex because pa- their results.
tients are heterogeneous, diagnosis of pneumonia is controversial
As already showed in our previous review (D’Amico 1998) and
and outcome depends on so many factors. Despite the ability of
confirmed in this updated meta-analysis both types of prophylaxis
antibiotic prophylaxis to reduce respiratory tract infections (RTIs)
have a strong protective effect on RTIs - with the effect being more
emerging with remarkable consistency across individual trials, the
marked when patients are treated with a protocol using topical
effect on mortality was statistically significant in only two trials.
plus systemic antibiotics. This effect looks consistent in all sub-
An historical examination of review articles and editorials in this
group analyses regardless of study design (Adequate / inadequate
area indicates that it was never fully realised that this could have
randomisation, double-blind / open studies). Overall, these results
been due to the small sample sizes of individual studies.
appear convincing even though it is acknowledged that no diag-
The meta-analysis reported here combines data across studies in nostic test or procedure is ideal to diagnose RTIs in ICU patients.
order to estimate treatment effects with more precision than is pos-
More importantly, this updated meta-analysis confirm that the
sible in a single study. The main limitation of this meta-analysis,
use of combination of topical and systemic antibiotics reduces
as with any overview, is that the patient population, the antibiotic
significantly overall mortality. This treatment effect looks impor-
regimen and the outcome definitions are not the same across stud-
tant from a clinical and public health point of view (in terms of
ies. Nonetheless, we believe that it provides the best global picture
the therapeutic implications for the care of ventilated patients in
of the effectiveness of the intervention despite some recent criti-
ICUs) and is also relevant from the scientific standpoint as it sug-
cisms on the quality of primary studies and their combination (van
gests the future directions that research in the field should take.
Nieuwenhove 2001) which we feel we have convincingly rejected
(Liberati 2001). Compared to the others six published meta-anal- Publication bias is unlikely to have influenced our results because
yses (Vanderbrouk-Gra 1991; SDD Group 1993; Heyland 1994; we made a thorough effort to trace unpublished studies and be-
Kollef 1994; Hurley 1995; Nathens 1999) we decided in our pre- cause the vast majority of trials did not show statistically signif-
viously published review (D’Amico 1998) to analyse separately icant reduction in mortality on their own. Moreover, inspection
trials testing a combination of systemic and topical antibiotics and of the relevant funnel plot for overall mortality reduction in pa-
those testing topical antimicrobials. Though there is no consen- tients receiving the combined treatment (see additional analysis,
sus on the best way to classify antibiotic prophylaxis regimens, it Figure 1) does not provide evidence of publication bias. Finally
seemed eventually more appropriate to consider the two groups if one ranks studies by their size, larger ones are those showing a
of trials as two distinct approaches to antibiotic prophylaxis. This statistically significant treatment effect on their own.
a moderate but humanly worthwhile effect of the treatment on
mortality. According to this systematic review, the combination
of topical and systemic antibiotics should be the standard against
AUTHORS’ CONCLUSIONS which new treatments should be tested. A logical next step for
future trials would seem the comparison of this protocol against
Implications for practice
a regimen based on a systemic antimicrobial only; only six trials
This systematic review indicates that a protocol testing a combina- included in this review chose this as their study design. It is un-
tion of topical and systemic antibiotics reduces the occurrence of likely, however, that one or more even large conventional trials
RTIs and overall mortality. These results were initially obtained in can satisfy the concerns of those who are afraid that antimicrobial
an individual patient meta-analysis reported elsewhere (D’Amico resistance may occur as a consequence of widespread use of an-
1998), which we have now updated using data reported in trials tibiotics. The recent trial by de Jonge et al. has now shown trials
published between 1999 and 2003. The yield of the treatment with innovative design are possible and that they allow for a more
expressed in terms of patients needed to be treated to prevent one reliable assessment of the occurrence of antibiotic resistance. We
infection and one death is substantial - five and 21 respectively hope that future trials should follow de Jonge’s example focussing
- and compares very favourably with several interventions largely on mortality and colonisation as main endpoints. In the meantime
used in clinical practice. Though 9/17 trials used an identical reg- a systematic analysis of the quality and reliability of existing data
imen, including polymyxin, tobramycin and amphotericin as the on resistance might be important to obtain a more comprehensive
topical combination and cefotaxime as the systemic component view of the yield of the treatment; we aim at concentrating on this
(Stoutenbeek 1984; Kerver 1988; Blair 1991; Finch 1991; Jacobs in future updates of this review.
1992; Rocha 1992; Abele-Horn 1997; Palomar 1997, de Jonge
2003), this review does not allow a unique regimen to be recom-
mended. The use of a prophylaxis testing topical antimicrobials
is, on the other hand, not warranted by available data.
ACKNOWLEDGEMENTS
Results of this review should be carefully considered by those who
have been skeptical about the effectiveness of antibiotic prophy- This systematic review would have not been possible without the
laxis, mostly on the ground of a harmful effect in terms of antibi- continuous and enthusiastic support of most of trials investigators.
otic resistance (Collard 2003). Moreover, important new infor- They collaborated in the different phases of this review up to the
mation has recently become available in a large randomised trial publication of our earlier review ( D’Amico 1998 ) by providing
(de Jonge 2003) that was the first to be formally designed to re- information on the design and conduct of their studies, check-
liably assess the occurrence of antibiotic resistance by randomis- ing the accuracy of the data before the final analysis, attending
ing ICUs rather than patients and monitoring the units for more a meeting where preliminary results were presented and, finally,
than two years after the inception of treatment use: de Jonge et al. reviewing earlier drafts of the manuscript.
reported that no patients was colonised with meticillin-resistant They names are listed below (in alphabetical order): M Abele-Horn
staphylococcus aureus, only 1% was colonised with vancomicin- 1997 (Ludwig-Maximilians-Universitat, Munich, Germany); SJA
resistant enterococcus and in 16% and 26% (in SDD and control Aerdts 1991 (Sophia Hospital, Zwolle, The Netherlands); P Blair
patients, respectively) colonization with gram negative bacteria re- 1991, B J Rowlands, H Webb and K Lowry (Royal Victoria Hos-
sistant to ceftazidime, ciprofloxacin, imipenem, polymyxin E and pital, Belfast, Northern Ireland); JP Boland 1991, D Sadler, A
tobramycin occurred (de Jonge 2003). Stewart and J Pollock (Health Science Center Charlestone, West
We believe that insufficient data on cost-effectiveness and antibi- Virginia University, West Virginia, USA); C Brun-Buisson 1989
otic resistance should stimulate future research rather than pre- (Hopital Henry Mondor, Creteil, France); FB Cerra 1992 (Uni-
venting the adoption of a seemingly effective intervention. The versity of Minnesota Hospital and Clinic, Minneapolis, USA);
impact of antibiotic prophylaxis on costs has so far been evaluated FR Cockerill 1992 and RL Thompson (Mayo Clinic, Rochester,
only rarely and, more importantly, in an improper way (the anal- Minnesota, USA); M Ferrer 1992 and A Torres (Servei de Pneu-
ysis being essentially based on comparisons of lengths of stay and mologia, Hospital Clinic, Barcelona, Spain); RG Finch 1991,
computation of charges due to antibiotic use). A proper economic P Tomlinson and G Rocker (Nottingham City Hospital, Not-
analysis is, on the other hand, likely to be difficult in a highly tingham, United Kingdom); H Gastinne 1992 (on behalf of the
specialised setting such as the ICU given that it is hard to quantify French study group on Selective Decontamination of the Di-
the relative contribution of single procedures. gestive Tract - France); P Gaussorgues 1991 (Hopital Eduoard
Herriot, Lyon, France); B Georges 1994 (Hopital de Rangueil,
Implications for research Toulouse, France); JMJ Hammond 1992, PD Potgieter (Groote
The number of RCTs on antibiotic prophylaxis so far conducted is Schuur Hospital, Cape Town, South Africa); S Jacobs (Univer-
substantial and provides now sufficient statistical power to detect sity Hospital of Wales, Cardiff, United Kingdom); S Jacobs and
M Zuleika (Riyadh Armed Forces Hospital, Riyadh, Saudi Ara-
bia); AJH Kerver 1988 (Sint Franciskus Hospital, Rotterdam,
Utrecht, The Netherlands); AM Korinek 1993 (Hopital Pitie-
Salpetriere, Paris, France); AN Laggner 1994 (Vienna General
Hospital, Vienna, Austria); FP Lenhart 1994 (University of Mu-
nich, Germany); W Lingnau (Leopold-Franzens-Universitat Inns-
bruck, Innsbruck, Austria); A Martinez-Pellus and J Rodriguez-
Rolda 1990 (University Hospital Virgen de la Arrixaca, El Pal-
mar, Murcia, Spain); M Palomar 1997 (Hospital Vall d’Hebron,
Barcelona, Spain); J Pugin 1991 and P Suter (University Hospi-
tal, Geneva, Switzerland); C Martin, B Quinio 1995 and J Al-
banese (Hopital Nord, Marseilles, France); LA Rocha 1992 (Hos-
pital Juan Canalejo, La Coruna, Spain); M Sanchez-Garcia 1992
(Hospital PPE Asturias, Alcala de Henares, Spain); CP Stouten-
beek 1994 (Academisch Ziekenhuis, Universiteit van Amsterdam,
Amsterdam, The Netherlands); C Ulrich 1989 and J E Harinck-
De Weerd (Westeinde Hospital, The Hague, The Netherlands); K
Unertl 1987 (Klinikum Grosshadern, Munich, Germany); J Ver-
haegen and C Verwaest (University Hospital Gasthuisberg, Leu-
ven, Belgium); J Wiener 1995 (Michael Reese Hospital, Chicago,
USA); R Winter 1992 (Queens Medical Centre University Hos-
pital, Nottingham, United Kingdom).
This review was originally initiated at the request of the French
Society of Intensive Care in preparation for the consensus confer-
ence on Selective Decontamination of the Digestive Tract (Paris,
December 1991) and led to the first publication in 1993 (SDD
Group 1993). It was then continued and updated between 1993
and 1998 through resources made available from the Mario Ne-
gri Institute, Milan, Italy and an unrestricted grant provided by
Hoechst Marion Roussel Italy, the sponsors had no control on
the protocol preparation, data analysis and manuscript review and
their support was sought after the decision of undertaking the re-
view by the Authors.
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de Jonge 2003 {published data only} sucralfate?. Wiener Klinische Wochenschrift 1994;106:15–9.
de Jonge E, Schultz J M, Spanjaard L, Bossuyt P M M, Vroom M
B, Dankert J, Kesecioglu J. Effects of selective decontamination of Lenhart 1994 {published data only}
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Ferrer 1992 {published and unpublished data}
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Finch 1991 {published and unpublished data}
Finch RG, Tomlinson P, Holliday M, Sole K, Stack C, Rocker G. Lingnau 1997b {published and unpublished data}
Selective decontamination of the digestive tract (SDD) in the pre- Lingnau W, Berger J, Javorsky F, Lejeune P, Mutz N, Benzer H. Selec-
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XVII International Congress Chemotherapy. 1991. tive, controlled trials. Journal of Trauma 1997;42:687–94.
Gastinne 1992 {published and unpublished data} Palomar 1992 {published data only}
Gastinne H, Wolff M, Delatour F, Faurisson F, Chevret S. A con- Palomar M, Barcenilla F, Alvarez F, Nava J, Triginer C, Jordà R, et
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Pneumatikos I, Koulouras V, Nathanail C, Goe D, Nakos G. Selec-
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Hammond 1992 {published and unpublished data} Pugin J, Auckenthaler R, Lew DP, Suter PM. Oropharyngeal decon-
Hammond JMJ, Potgieter PD, Saunders GL, Forder AA. Double tamination decreases incidence of ventilator-associated pneumonia.
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intensive care. Lancet 1992;340:5–9. Quinio 1995 {published and unpublished data}
Jacobs 1992 {published and unpublished data} Quinio B, Albanèse J, Bues-Charbit M, Viviand X, Martin C. Se-
∗
Jacobs S, Foweraker JE, Roberts SE. Effectiveness of selective de- lective Decontamination of the digestive tract in multiple trauma
contamination of the digestive tract (SDD) in an ICU with a policy patients: prospective, double blind, randomised, placebo-controlled
encouraging a low gastric pH. Clinical Intensive Care 1992;3:52–8. study. Chest 1996;109:765–72.
Rocha 1992 {published and unpublished data} Barret 2001 {published data only}
Rocha LA, Martin MJ, Pita S, Paz J, Seco C, Margusino L, et Barret JP, Jeschke MG, Herndon DN. Selective decontamination of
al.Prevention of nosocomial infection in critically ill patients by se- the digestive tract in severely burned pediatric patients. Burns 2001;
lective decontamination of digestive tract. Intensive Care Medicine 27:439–45.
1992;18:398–404. Bion 1994 {published data only}
Rodriguez-Rolda 1990 {published and unpublished data} Bion JF, Badger I, Crosby HA, Hutchings P, Kong KL, Baker J, et
Rodrìguez-Roldàn JM, Altuna-Cuesta A, Lòpez A, Carrillo A, Gar- al.Selective decontamination of the digestive tract reduces Gram-
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Bouter 2002 {published data only}
Sanchez-Garcia 1992 {published and unpublished data}
Bouter H, Schippers EF, Luelmo SAC, Verteegh MIM, et al.No effect
Sanchez-Garcia M, Cambronero JA, Lopez J, Cerda E, Rubio J, et
of preoperative selective gut decontamination on endotoxemia and
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Respiratory and Critical Care Medicine 1998;158:908–16. Flaherty 1990 {published data only}
Flaherty J, Nathan C, Kabins SA, Weinstein RA. Pilot trial of selective
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Stoutenbeek CP, Van Saene HKF, Miranda D R, Zandstra DF. The care unit. Journal of Infectious Diseases 1990;162:1393–7.
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Medicine 1984;10:185–92. Garbino J, Lew DP, Romand JA, Hogonnet S, Auckenthaler R, Pittet
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Stoutenbeek C P, Van Saene H K F, Little R A, Whitehead A. The trolled trial in patients treated by severe digestive decontamination.
effect of selective decontamination on the digestive tract on mortality Intensive Care Medicine 2002;28:1708–17.
in multiple trauma patients.
Hellinger 2002 {published data only}
Ulrich 1989 {published and unpublished data} Hellinger WC, Yao JD, Alvarez S, Blair JE, et al.A randomized,
Ulrich C, Harinck-deWeerd JE, Bakker NC, Jacz K, Doornbos L, prospective, double blinded evaluation of selective bowel decontam-
de Ridder VA. Selective decontamination of the digestive tract with ination in liver transplantation. Transplantation 2002;73:1904–9.
norfloxacin in the prevention of ICU-acquired infections: a prospec- Hunefeld 1989 {published and unpublished data}
tive randomized study. Intensive Care Med 1989;15:424–31. Hunefeldt G. [Klinische Studie zur selectiven Darmdekolonisation
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Verwaest 1997 {published and unpublished data} nization of upper respiractory tract in a multidisciplinary ICU. Crit-
Verwaest C, Verhaegen J, Ferdinande P, Schets M, Van der Berghe ical Care Medicine 1994:141.
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decontamination in 600 mechanically ventilated patients in a mul- Luiten EJ, Hop WC, Lange JF, Bruining HA. Controlled clinical
tidisciplinary intensive care unit. Critical Care Medicine 1997;25: trial of selective decontamination for the treatment of severe acute
63–71. pancreatitis. Annals of Surgery 1995;222:57–65.
Wiener 1995 {published data only} Martinez 1994 {published data only}
Wiener J, Itokazu G, Nothan C, Kabins SA, Weinstein RA. A ran-
∗
Martinez PAE, Bru M, Jara P, Ruiz J, Sanmiguel MT, Garcia PT.
domized, double-blind, placebo-controlled trial of selective digestive Does cefotaxime prevent early pneumonia in trauma patients receiv-
decontamination in a medical-surgical intensive care unit. Clinical ing pharyngeal decontamination?. Medicina Intensiva 1994;18:245–
Infectious Diseases 1995;20:861–7. 9.
Martinez-Pellus 1993 {published data only}
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digestive tract in intensive care and its effect on nosocomial infection.
Critical Care Medicine 1993;2:1684–91.
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Nardi 2001 {published data only}
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Rayes 2002 {published data only} Selective decontamination of the digestive tract. An overview. Chest
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A, et al.Decontamination in the prevention of anastomotic insuffi- ical quality on study conclusions. JAMA 2001;286:2544–5.
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colonisation and infections after oesophageal resection. Lancet 1990; Stoutenbeek CP, Van Saene HKF, Miranda DR, Zandstra DF. The
335:704–7. effect of selective decontamination of the digestive tract on coloniza-
Zwaveling 2002 {published data only} tion and infection rate in multiple trauma patients. Intensive Care
Zweveling JH, Maring JK, Klompmaker IJ, Haagsma EB, et Medicine 1994;10:185–92.
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tionship between methodological trial quality and the effects of se-
References to ongoing studies lective digestive decontamination on pneumonia and mortality in
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Anonymous {unpublished data only}
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Additional references
References to other published versions of this review
Brazzi 1992
Brazzi L, Liberati A. A review of design and conduct of the available
studies on selective decontamination of the digestive tract (SDD). D’Amico 1998
Rean urg 1992;1:501–7. D’Amico R, Pifferi S, Leonetti C, Torri V, Tinazzi A, Liberati A, et
Collard 2003 al.Effectiveness of antibiotic prophylaxis in critically ill adult patients:
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Internal Medicine 2003;138:494–501. SDD Group 1993
Fagon 1996 SDD Trialists’ Collaborative Group. Meta-analysis of randomised
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Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Abele-Horn 1997
Methods Randomised study blinded for radiologic diagnosis

Randomisation method: list block randomised assignments mantained by the main investigator. Open.
Accrual period: not available
Participants Eligibility criteria: intubation within 24 hrs of admission, expected ventilation for at least 4 days, first
microbial culture within 36 hrs of admission
Exclusion criteria: transfer from other hospitals, evidence of infection, prior antibiotic therapy, ARDS,
leucopenia, myelosuppression
Patients enrolled in the study: 125; 37 pts were excluded leaving 88 pts for analysis
Percentage of ventilated patients: 100%
ICU length of stay, mean: 19.3 days
Type of admission diagnosis: surgical unscheduled=16% trauma=84%
Severity score on admission: APACHE II mean=17, ISS not available
Percentage of immunocompromised patients:not available
Percentage of patients treated with systemic antibiotic therapy (not stated by protocol) in the first 3 days:
not available
Stress ulcer prophylaxis applied: sucralfate 1gx4 to all pts
Interventions Group A, Treatment: -Polymyxin 100mg, Tobramycin 80mg, Amphotericin B 500mg applied orally 4
times a day as a 2% paste during the ICU stay
-Cefotaxime 2gx3 iv x 3 days
Group B, CTR:
-No prophylaxis
Antibiotic prophylaxis was performed only for abdominal, orthopedic and neurologic surgery
Outcomes Respiratory infections (acquired pneumonia):

Diagnosis was based on Clinical Pulmonary Infection Score as defined by Pugin 1991: new pulmonary
infiltrate on x-Ray, increasing amount of tracheal secretions containing > 3x10ˆ4 granulocytes/mcl and
at least two of the following: temperature > 38.5°C, WBC>12,000/mm3 or <4,000/mm3, decrease in
PaO2 requiring an increase in FiO2. Besides a bacteriological confirmation is required: tracheal aspirates
yielding bacteria >10ˆ4 CFU/ml and granulocytes >10/field
Mortality: in ICU
Notes Data about 37 excluded patients are not available
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear D - Not used
Aerdts 1991
Methods Randomised study with 3 arms (1 treatment arm versus 2 control arms), blinded for respiratory diagnosis
Randomisation method: sealed envelopes, permuted block method. Blind
Accrual period: May 86-Sept 87
Participants Eligibility criteria: expected ventilation for at least 5 days, inclusion within 24 hrs of admission
Exclusion criteria: age <16 yrs, pregnancy, allergy to one of the component of the regimen
Patients enrolled in the study: 88
ICU length of stay, median: 16 days
Type of admission diagnosis: medical=40% surgical scheduled=6% surgical unscheduled=20%
trauma=34%
Severity score on admission: APACHE II mean=21.8, ISS not available
Percentage of immunocompromised patients: 4.6%
Treatment =35% CTR=80%
Stress ulcer prophylaxis applied: antiacids until enteral feeding was possible
Interventions Group A, CTR 1:

-No prophylaxis, infections of unknown origin were treated with ampicillin+gentamicin.
Group B, CTR 2:
-No prophylaxis, infections of unknown origin were treated with cefotaxime+gentamicin and metronida-
zole if indicated.
Group C, Treatment:
-Polymyxin E 200mg, Norfloxacin 50mg, Amphotericin B 500mg applied enterally 4 times a day and, as
a 2% paste, to the oropharynx until extubation
-Cefotaxime 500mgx3 iv x 5 days. Infections of unknown origin were treated as group B.
Outcomes Respiratory infections (acquired pneumonia and tracheobronchitis):

Diagnosis of tracheobronchitis was based on: positive culture of the tracheal aspirate and a Gram stain
showing many leukocytes as well as the causative organism, associated with 2 of the following: temperature
>38°C, WBC>12000/mm3, purulent tracheal aspirate
Diagnosis of pneumonia was based on: a new and persistent pulmonary infiltrate on x-Ray and criteria
of tracheobronchitis
Mortality: in ICU
Notes The study presents 2 control groups that are considered as a whole in metanalysis
Personal contact with the main investigator provided data about 32 patients who were excluded from the
published paper (16 early extubation, 7 early death, 5 protocol violation, 3 other, 1 unknown); these data
are considered in analysis
Risk of bias
Bergmans 2001
Methods Randomised, double blind, placebo-controlled study
Participants Elegibility criteria: intubation within 24 hrs of admission and need for mechanical ventilation with an
expected duration > 2 hours
Esclusion criteria: age<16 yr.
ICU length of stay, median treatment group: 13 days; median control A group: 15 days, median control
B group: 12 days
Type of admission diagnosis:
Medical=35%
Surgery=39%
Trauma=19%
Neurology=6%
Other=1%
Severity score on admission: APACHE II mean=21,4, ISS not available
Percentage of immuncompromised patients: 2%
Percentage of patients treated with systematic antibiotic therapy at admission:
Treatment: 47% CTR=42%
Stress ulcer prophilaxis applied: Treatment = 61%
Control = 76%
Interventions Group A, Treatment:

Orabase with 2% gentamicin, 2% colistin and 2% vancomycin
Orabase was applied in the buccal cavities on a gloved finger every 6 h.
The application of Orabase was started within 24 h of intubation.
Application of treatment was limited to 21 d.
Group B, CTR1
no prophilaxis
-this group was studied in ICU in which there was the presence of patients receiving topical antimicrobial
prophilaxis
Group C: CTR2
no prophilaxis
This control group was studied in ICU in which where no topical antimicrobial prophylaxis was used
Outcomes Ventilator-associated pneumonia (VAP); diagnosis of VAP was established on the basis of positive quanti-
tative cultures from BAL (cutoff point >=10ˆ4 colony-forming units [cfu]/ml) or PSB (cutoff point>=10ˆ3
cfu/ml), or a positive blood culture unrelated to another source of infection, or a positive culture from
pleural fluid in the absence of previous pleural instrumentation.
Mortality: in hospital
Notes
Risk of bias
Bergmans 2001 (Continued)
Blair 1991
Methods Randomised study

Randomisation method: sealed envelopes. Blind
Accrual period: Sept. 1988 - Jan 1990
Participants Eligibility criteria: all admitted pts who do not fulfil the exclusion criteria
Exclusion criteria: patients discharged within 48 hrs of ICU admission; admission from CCU; pts expected
to die after 6 hrs of ICU admission; pts with discharge anticipated within 48 hrs but remaining more than
48 hrs; drug overdose; security pts; age <18yrs; pts not randomised within 6 hrs of admission; readmission
to ICU; burns; miscellaneous
Length of stay in ICU, median: 5 days
trauma=40%
Severity score on admission: APACHE II mean=14.4, ISS mean=24.8
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3
days: treatment =42% CTR=74%
Stress ulcer prophylaxis applied: all patients received ranitidine iv plus antiacid therapy if gastric pH was
low
Interventions Group A, CTR:

-Standard antibiotic therapy (no prophylaxis)
Group B, Treatment:
-Polymyxin 100mg, Tobramycin 80 mg, Amphotericin B 500 mg applied enterally 4 times a day and, as
a 2% gel, to the oropharynx
-Cefotaxime 50 mg/kg/day iv x 4 days
Outcomes Respiratory infections (pneumonia acquired after 48 hrs); Diagnosis of infection was based on the fulfill-
ment of Criteria I or Criteria II.
Criteria I: temperature >38.5°C on two separate occasion, WBC >12x10ˆ9/l or <4x10ˆ9 and a new
pulmonary infiltrate on x-Ray.
Criteria II: temperature >37.5°C, a new pulmonary infiltrates on x-Ray, purulent sputum and drop in
PaO2.
Mortality: in ICU
Notes Personal contact with the main investigator provided data about 75 patients who were excluded from the
published paper for short length of stay; these data are considered in analysis
Blair 1991 (Continued)
Risk of bias
Boland 1991
Methods Randomised, placebo-controlled, double-blind study

Randomisation method: computer generated randomisation directed by the pharmacy department. Blind
Accrual period: Apr 89-Mar 91
Participants Eligibility criteria: all multiple traumatised patients, intubated at the time of admission and likely to stay
intubated at least 5 days
Exclusion criteria: patients who did not remain intubated for 5 days
Type of admission diagnosis: trauma=100%
Percentage of immunocompromised patients: 0%
days: treatment=0% CTR=0%
Stress ulcer prophylaxis applied: H2-blockers or sucralfate (78%).

-Placebo
Group B, Treatment:
-Polymyxin 100mg, Tobramycin 80 mg, Nystatin 1,600,000 units applied enterally 4 times a day and, as
a 2% paste plus 60,000 units of Nystatin, to the oropharynx until extubation or discharge
-Cefotaxime 1g x3 iv for the first 3 days
Outcomes Respiratory infections (acquired pneumonia and tracheobronchitis).

Diagnosis of infection was based on:
positive sputum culture for bacteria, fever>38°C and leukocytosis (>10,000 WBC/mm3 of blood)
Mortality: in ICU
published paper (20 early extubation, 3 early death); these data are considered in analysis
Risk of bias
Brun-Buisson 1989
Methods Randomised trial

Randomisation method: odd and even birth year technique. Open
Accrual period: Apr 87-May 87
Participants Eligibility criteria: patients with an admission SAPS > 2 and staying in the ICU more than 48 hrs
Exclusion criteria: patients with severe neutropenia routinely receiving oral antibiotic prophylaxis
Length of stay in ICU, median: 3.5 days
Type of admission diagnosis: medical 75% surgical unscheduled 23% trauma 2%
Severity score on admission: SAPS mean=10.4, ISS not available
Percentage of immunocompromized patients: 12.8%
Stress ulcer prophylaxis applied: none

-Polymyxin E 50mg, Neomycin 1g, Nalidixic acid 1g, applied orally and enterally 4 times a day until
discharge
-Oropharyngeal disinfectant in intubated patients
Group B, CTR:
-Oropharyngeal disinfectant in intubated patients
Outcomes Respiratory infections (pneumonia acquired in the ICU or within 48 hrs from discharge).
purulent sputum or tracheal aspirate associated with a new and persistent pulmonary infiltrate on x-Ray
and the culture of at least 10ˆ9 CFU/l from a protected wedged catheter sample of bronchial aspirate,
temperature >38°C, WBC >10x10ˆ9/l
Mortality: in ICU
Notes Setting: acute and intermediate areas of a medical ICU

published paper (7 early death, 1 tranferring, 39 other); these data are considered in analysis
Risk of bias
Cerra 1992

Accrual period: Sept. 1988 - Jan 1990
Participants Eligibility criteria: admission within 48 hrs from surgery, trauma or other acute event, expected stay at least
5 days, hypermetabolism (VO2 >140 ml/m2 or urinary nitrogen excretion >10 g/day) without progressive
MOSF (normal transaminases, stable bilirubine and creatinine)
Exclusion criteria: Cirrhosis, allergy to used drugs, chemo-radiotherapy, progressive MOSF, gastrointesti-
nal leak or fistula
Percentage of ventilated patients: not available
ICU length of stay, median: not available
Type of admission diagnosis: surgical=96% trauma=4%
Severity score on admission: not available
Percentage of immunocompromized patients: not available
days: not available
Stress ulcer prophylaxis applied: not available

-Norfloxacin 500mg x3, Nystatin 1 milion U x 4 applied enterally until discharge
Group B, CTR:
-Placebo
Outcomes Respiratory infections: not evaluable

Mortality
published paper for short length of stay); these data are considered in analysis
Risk of bias
Cockerill 1992
Methods Randomised study blinded for respiratory diagnosis. Intention to treat

Randomisation method: randomisation table at a remote site in the pharmacy. Blind
Accrual period: 1986-1989
Cockerill 1992 (Continued)
Participants Eligibility criteria: all patients admitted to the mixed ICU if their condition suggested a prolonged stay
(>3 days), age >18yrs
Exclusion criteria: age <18 yrs, pregnancy, allergy to one of the component of the regimen, infections,
antibiotic therapy 24hrs before randomisation
ICU length of stay, median: 4.5 days
trauma=34%
Severity score on admission: APACHE II mean=19.4, ISS mean 24.3
Stress ulcer prophylaxis applied: H2-blockers (80%)

- No prophylaxis
Group B, Treatment:
-Gentamycin 80mg, Polymyxin B 100mg, Nystatin 2,000,000 units, applied enterally and as a 2% paste
to the oropharynx 4 times a day during the ICU stay
-Cefotaxime 1g/8 hrs iv for the first 3 days
Outcomes Respiratory infections (only acquired infections).

Diagnosis of pneumonia was based on clinical and laboratory criteria:
a new or progressive pulmonary infiltrate, purulent secretions, isolation of a potential pathogen and fever
with or without leukocytosis.
Diagnosis of trachobronchitis was based on:
the presence of increased purulent endotracheal secretions requiring frequent suctioning and the presence
of a potential pathogen
Notes
Risk of bias
de Jonge 2003
Methods Randomised study. Randomisation method:computer-generated random-number codes kept in sealed

envelopes
de Jonge 2003 (Continued)
Participants Eligibility criteria: adult patients admitted to ICU: with an expected stay of at least 72 h and an expected
duration of mechanical ventilation of at least 48 h
Exclusion criteria:
previous admission in ICU whithin 3 months ipersensitivity to study medication, pregnancy and perceived
imminent death
Number of patients enrolled in the study: 934
Length of stay in ICU: median SDD group=6.8 days
control group=8.5 days
Type of admission diagnosis:
medical: 41%
surgical urgent: 25%
surgical elective: 34%
Severity score at admission:
APACHE II mean=18.7
SAPS II in SDD group mean=17.9
SAPSII in control group mean= 17.1
Percentage of immunocompromised patients
SDD group=2.4%
control group=1.7%
Information on prescribed antibiotics per 1000 patients available in the main publication
No stress ulcer prophylaxis by protocol
Interventions SDD group:

topical plus systemic treatment
Topical:
oral paste containing 2% polymyxin E, 2% tobramycin, 2% amphotericin
500 mg amphotericin B through gastric tubes
Systemic: Cefotaxime 1000 mg 4 times daily for 4 days
Control group:
No antibiotic prophylaxis; antibiotic treatment based on clinical needs
Outcomes Colonisation,
antibiotic resistence and ICU and hospital mortality
Notes Patients were allocated to either an SDD or a control unit to prevent cross-colonisation between SDD
and ICU control patients. Standard care was the same in the two units.
Risk of bias
Allocation concealment? Yes A - Adequate
Ferrer 1992

Randomisation method: computer generated table. Open
Accrual period: Jan 91-Mar 92
Participants Eligibility criteria: all mechanically ventilated patients expected to remain intubated for more than 3 days
Exclusion criteria: patients with HIV-related diseases or treated with antineoplastic chemotherapy as well
as patients who received transplants, extubation or death within 72 hrs
Number of patients enrolled in the study:101
Percentage of ventilated patients:100%
Length of stay in ICU, median:7,5 days
Type of admission diagnosis: medical 66% surgical scheduled 6.9% surgical unscheduled 6.9% trauma
=19.8%
Severity score admission: SAPS mean=12.1, ISS not available
Percentage of immunocompromised patients:0%
days: not available
treatment=73% CTR=74%
Stress ulcer prophylaxis applied: sucralfate except in pts with paralytic ileus or with upper gastrointestinal
bleeding, who were treated with ranitidine

-Polymyxin E 100mg, Tobramycin 80 mg, Amphotericin B 500 mg applied enterally and, as a 2% paste,
to the oropharynx 4 times a day until extubation or death
-Cefotaxime 2gr/day iv for the first 4 days or others if required
Group B, CTR:
-Placebo
-Cefotaxime 2gr/day iv for the first 4 days or others if required*
*patients infected on admission received adeguate antibiotic treatment instead of cefotaxime
Outcomes Respiratory infections (pneumonia acquired after 4 days of mechanical ventilation)

Diagnosis of infection was based on clinical criteria plus brush or BAL confirmation.
Clinical criteria: new or progressive pulmonary x-Ray infiltrate for at least 48 hrs, purulent tracheal
secretions, temperature>38.5 °C and leukocytosis>=12x10ˆ9 WBC/l or leukopenia<=4x10ˆ9
Mortality: in ICU
Notes Personal contact with the main investigator provideded data abaut 21 patients who were excluded from
the published paper (14 early extubation, 6 early death, 1 trasfer); these data are considered in analysis
Risk of bias
Finch 1991

Randomisation method: sealed envelopes. Randomisation series made available to the hospital Pharmacy
only. Blind
Accrual period: Aug 87-Sept 89
Participants Eligibility criteria: all patients whose length of stay was > 60 hrs, age >16 yrs
Exclusion criteria: none
Length of stay in ICU: not available
Type of admission diagnosis: medical 59% surgical scheduled 27% surgical unscheduled 10% trauma=4%

-Polymyxin B 100mg, Gentamycin 120mg, Amphotericin B 500 mg applied enterally and, as a 2% paste,
to the oropharynx 4 times a day
-Cefotaxime 1gx3 iv for the first 4 days
Group B, CTR:
-Conventional antibiotic therapy
Outcomes Respiratory infections (acquired pneumonia)

Diagnosis of pneumonia was based on:
tracheal aspirate with numerous leukocytes associated with any of the following: a single bacterial species
with a growth density > 10ˆ5 CFU, diagnosis of septicemia, clinical signs of pulmonary infections (fever,
leukocytosis and appropriate radiological findings)
Mortality: in ICU
Notes Personal contact with the main investigator provided information about mortality on 5 patients who were
excluded from the published paper (1 early extubation, 2 early death, 1 transferring, 1 unknown); these
data are considered in the analysis. Data about respiratory infections in patients excluded from published
paper are not available
Risk of bias
Gastinne 1992
Methods Randomised, placebo-controlled, double-blind, multicenter (15 ICUs) study. Intention to treat
Randomisation method: a randomised list of consecutive treatment assignments, performed separately in
each unit. Open
Accrual period: Feb 90-Jun 90
Participants Eligibility criteria: all patients > 15 yrs who required mechanical ventilation and with intubation performed
no more than 48 hrs before randomisation
Exclusion criteria: patients with ventilation for less than 24 hrs, drug or alcohol overdose, neutropenia
(WBC<500/mm3), SAPS > 24 or GCS < 4, chronic degenerative central nervous system disease or spinal
cord injury above level of C4, acute severe entheropathy, pregnancy, participation in another ongoing
clinical trial, refusal of consent, pts with conditions in which survival was strongly related to status on
admission
Length of stay in ICU, median: 12days
Severity score on admission: SAPS mean=13.5, ISS not available GCS mean=11.7
Stress ulcer prophylaxis applied: sucralfate (43% pts), H2-blockers (13% pts)

-Placebo
Group B, Treatment:
-Tobramycin 80mg, Polymyxin E 100mg, Amphotericin B 100 mg applied enterally and, as a 2% paste,
to the oropharynx 4 times a day throughout the period of ventilation
Outcomes Respiratory infections (pneumonia diagnosed within 48 hrs and acquired):

purulent tracheal aspirate, temperature >38,5°C, peripheral leukocytosis (>10,000 WBC/mm3 of blood)
and a new and persistent infiltrate on the chest film. Brushing was recommended but not mandatory.
Notes
Risk of bias
Gaussorgues 1991
Methods Randomised study. Intention to treat

Randomisation method: odd-even numbers. Open
Accrual period: Sept.88-Sept.89
Participants Eligibility criteria: all patients admitted to the ICU, who required mechanical ventilation and inotropic
drugs for hemodinamic reasons
Exclusion criteria: neutropenia
ICU length of stay: not available
Type of admission diagnosis: medical=83% surgical scheduled=17% (all patients were infected on admis-
sion)
Severity score on admission: SAPS mean=17.5
Percentage of immunocompromised patients: not available
Stress ulcer prophylaxis applied: sucralfate 4 g to all patients

-Polymyxin E 36mg, Gentamycin 80mg, Vancomycin 50mg, Amphotericin B 500 mg applied enterally
4 times a day until extubation
- Amphotericin B, Clorexidine applied orally 4 times a day
- systemic antibiotic therapy
Group B, CTR:
- Amphotericin B, Clorexidine applied orally 4 times a day
- systemic antibiotic therapy

Mortality: in ICU
Notes All patients were infected on admission.

Data about respiratory infections are not provided
Risk of bias
Georges 1994
Methods Randomised, placebo-controlled study

Accrual period: Jun 1990-April 1992
Participants Eligibility criteria: Polytrauma, expected mechanical ventilation for at least 4 days, age>18 years
Exclusion criteria: Hypersensitivity to the used agents, protocol violation, obesity, ventilation <4 days, pts
on mechanical ventilation 2 days before admission, severe maxillo-facial lesions
Patients enrolled in the study: 138, but only 64 pts were analysed
Length of stay in ICU, mean: 33 days
Percentage of ventilated pts: 100%. Length of ventilation, mean: 16 days
Type of admission diagnosis: trauma 100%
Severity score on admission: APACHE II mean=15, ISS=41
Percentage of patients treated with systemic antibiotic therapy in the first 3 days: almost 100%
Stress ulcer prophylaxis: H2-blockers
Interventions Group A:
Treatment: Polymyxin E 75 mg, Netilmicin 150 mg, Amphotericin B 400 mg applied enterally 4 times a
day and, as a 2% paste, to the oropharynx until extubation
-Systemic antibiotic prophylaxis was free
Group B: CTR
- Placebo
- Systemic antibiotic prophylaxis was free
Outcomes Respiratory infections (acquired pneumonia)

Fever >38.5 °C, leukocytosis > 12000/mm3, new infiltrates in the chest X-rays, purulent pulmonary
secretions, positive bacteriologic findings (>10ˆ3 CFU/ml) obtained through a protected catheter
Mortality: in ICU and hospital
Notes Antibiotic prophylaxis was free and almost all patients of both groups were treated with systemic antibi-
otics.
74 potentially eligible patients were excluded from analysis; it is not evident if this happened before or
after randomisation; these data are not available
Risk of bias
Hammond 1992

Randomisation method: computer generated random numbers. Open
Accrual period: Jan 89-Dec 90
Participants Eligibility criteria: expected intubation for longer than 48 hrs and stay in ICU for at least 5 days
Exclusion criteria: hypersensitivity to the study drugs, patients with asthma, drug overdose and patients
admitted electively after surgery
Stress ulcer prophylaxis applied: none, H2-blockers only to high risk patients

-Polymyxin E 100mg, Tobramycin 80mg, Amphotericin B 500 mg applied enterally and, as a 2% gel, to
the oropharynx 4 times a day until 48 hrs after extubation
-Cefotaxime 1gx3 iv for the first 3 days to patients untreated on admission
Group B, CTR:
-Placebo
-Cefotaxime 1gx3 iv for the first 3 days to patients untreated on admission
Outcomes Respiratory infections (infections acquired after 48 hrs)

Diagnosis of pneumonia was based on:
a new infiltrate on x-Ray and purulent bronchial secretions with many leukocytes, temperature >38°C,
WBC>10ˆ10/l, substantial number of organism on gram stain with a pure growth culture from tracheal
aspirate, deterioration of gas exchange of >2 kPa.
Diagnosis of bronchial infection was based on:
all the previous criteria except the X-Ray changes
Notes Personal contact with the main investigator provided data on 82 patients who were excluded and sepa-
rately considered in the published paper (78 short stay, 3 protocol violation, 1 unknown); these data are
considered in the analysis
Risk of bias
Jacobs 1992

Accrual period: Jul 89-Aug 90
Participants Eligibility criteria: expected stay in ICU > 3 days

ICU length of stay, median: unknown
Type of admission diagnosis: medical=25% surgical=57% trauma=18% (high percentage of neurologic
and neurosurgical patients 52%)
Percentage of immunocompromised patients: unknown
days: next to 100%
Stress ulcer prophylaxis applied: policy of maintenance a low gastric pH, H2-blockers only if peptic ulcer
or steroid therapy (33%), sucralfate 4g to all patients not on enteral feeding
Interventions Group A,Treatment:

-Polymyxin E 100mg, Tobramycin 80 mg, Amphotericin B 500 mg applied orally and enterally 4 times
a day until extubation
Group B, CTR:
-No prophylaxis

alveolar infiltrates on 2 or more chest X-rays, moderate or copious purulent tracheal aspirate, rectal
temperature >38.4°C, leucocytosis >13x10ˆ9/l, a heavy growth of organisms from tracheal aspirate with
a high polymorphonuclear leucocytes/epithelial cell ratio
Mortality
Notes Almost 100% of patients received systemic antibiotic therapy on admission.

published paper (11 short stay in ICU, 1 HIV+); these data are considered in the analysis
Risk of bias
Jacobs 2 unpublished

Randomisation method: sealed envelopes. blind
Accrual period: May 94-Mar 95
Participants Eligibility criteria: expected need of ventilation for at least 3 days

Exclusion criteria: Death or extubation before 3 days
ICU length of stay, median: unknown
Type of admission diagnosis: medical=58% surgical=21% trauma=21%
Severity score on admission: APACHE II modified with best GCS mean=16.4, ISS mean=35.9
Stress ulcer prophylaxis applied: none

-Polymyxin E 100mg, Gentamycin, Amphotericin B 500 mg
Group B, CTR:
-No prophylaxis
Outcomes Respiratory infections (pneumonia acquired after 48hrs):

diagnosis was based on Clinical Pulmonary Infection Score as defined by Pugin 1991
Mortality: follow up
Notes Personal contact with the main investigator provided data about 13 patients who were excluded (3 early
extubation, 9 early death, 1 unknown); these data are considered in the analysis
Risk of bias
Kerver 1988

Randomisation method: odd/even numbers. Open
Accrual period: Jan 85-May 86
Participants Eligibility criteria: all patients admitted to the surgical ICU who required care >5 days
ICU length of stay, not available
Kerver 1988 (Continued)
Type of admission diagnosis: surgical=60% trauma = 28% other =12%

days: about 85%

- Polymyxin E 200mg, Tobramycin 80 mg, Amphotericin B 500 mg applied orally and enterally 4 times
a day
- Oral disinfectant
- Cefotaxime 50-70 mg/kg/day iv x 5-7 days
Group B, CTR:
- Oral disinfectant
Outcomes Respiratory infections (primary pneumonia and pneumonia acquired after 48hs)
Diagnosis of infection was based on X-ray findings and the presence of three of the following criteria on the
same day: rectal temperature >38.5°C for at least 12 hrs, WBC count >10x10ˆ3 or <4x10ˆ3/mcl, at least
3% band forming granulocytes, unexplained decrease in platelet count <100,000/mcl, deterioration of
renal function due to acute tubular necrosis, unexplained decrease in systolic blood pressure of >30mmHg,
progressive respiratory failure
Mortality
Notes
Risk of bias
Korinek 1993
Methods Randomised, placebo-controlled, double-blind, dual-centre study

Randomisation method: randomisation performed by the hospital pharmacist on each unit separately.
Blind
Accrual period: Mar 89-Sep 90
Participants Eligibility criteria: all comatose patients with emergency admission to two neurosurgical ICUs and intu-
bated within 24 hrs for at least 5 days, age > 16 yrs
Exclusion criteria: age <16 yrs, known immunosuppression, antibiotic treatment during the 2 weeks
preceding ICU admission, serious injury of oropharyngeal mucosa or epistaxis, abnormal chest X-ray on
admission, extubation or infection occurring within the first 5 days of neurosurgical care
Korinek 1993 (Continued)
Length of stay in ICU, mean: 26 days

Type of admission diagnosis: surgical scheduled 11% surgical unscheduled 39% trauma 50%
Stress ulcer prophylaxis applied: sucralfate (32%), antiacids (14%), H2-blockers (20%) until enteral
feeding was started

-Polymyxin E 100mg, Tobramycin 80mg, Amphotericin B 500 mg applied enterally and, as a 2% paste,
to the oropharynx 4 times a day for 15 days
-Vancomicin x os
Group B, CTR:
-Placebo
The nonabsorbable antibiotics were discontinued if any infection requiring a parenteral antibiotic treat-
ment occurred and at the time of patient’s extubation
Outcomes Respiratory infections (pneumonia acquired after 5 days)

fever >38.5°C, leukocytosis > 12,000 cells/mm3, purulent sputum, new and persistent infiltrates on chest
X-ray and a culture of >10ˆ3 CFU/ml obtained with either brush or plugged telescoping catheter
Mortality: in ICU
Notes Setting: neurosurgical ICU

Personal contact with the main investigator provided data about 68 patients who were excluded from
the published paper (early extubation, early death, protocol violation, transferring, other); these data are
Risk of bias
Laggner 1994

Randomisation method: computer generated randomisation in time blocks. Open
Accrual period: Aug 87-Nov 90
Laggner 1994 (Continued)
Participants Eligibility criteria: expected ventilation for 5 days, age >18 yrs and <80 yrs, acute onset of respiratory
failure
Exclusion criteria: age <18 yrs and >80 yrs, bleeding of the nasopharynx and of the upper gastrointestinal
tract on admission, stress ulcer prophylaxis with other drug therapy than sucralfate, mechanical ventilation
for less than 5 days, patients on enteral nutrition or with known allergy to sucralfate or gentamicin
Number of patients enrolled in the study: 88, but only 67 pts were analysed
Length of stay in ICU, mean: 28.8 days
days: 100%
Stress ulcer prophylaxis applied: sucralfate

-Gentamycin 40mg, Amphotericin B 100 mg applied to the oropharynx 4 times a day until extubation
-Oropharyngeal disinfectant
-Aminopenicillin and Clavulanic Acid or other appropriate regimens
Group B, CTR:
-Placebo
-Amphotericin B 100mg
-Oropharyngeal disinfectant
-Aminopenicillin and Clavulanic Acid or other appropriate regimens

appearance of a new infiltrate on the chest film with concomitant tracheal colonisation, fever >38°C and
>15,000 or <5,000 WBC/mm3 of blood
Mortality: in ICU.
Notes Data about 21 patients who were excluded from the published paper (18 short mechanical ventilation, 3
early enteral nutrition) are not available
Risk of bias
Lenhart 1994
Methods Randomised, placebo-controlled, double-blind, double centre study

Randomisation method: unknown
Accrual period: Apr 89-Mar 91
Participants Eligibility criteria: expected stay in ICU > 2 days and at least one risk factor for infection
Exclusion criteria: unknown
Patients enrolled in the study: 546, 19 pts were excluded leaving 527 pts for analysis
ICU length of stay, not available
Type of admission diagnosis: not available
not available
Stress ulcer prophylaxis applied: sucralfate to all patients

-Polymyxin B 50mg, Gentamycin 80mg, applied nasally, orally and enterally 4 times a day during the
ICU stay
-Ciprofloxacin 400 mg x2 iv x 4 days to uninfected patients
Group B, CTR:
- Placebo applied nasally, orally and enterally
- Placebo iv to uninfected patients

Mortality
Notes Data about 19 patients excluded from the published paper are not available.
Data about respiratory infections are not evaluable
Risk of bias
Lingnau 1997
Methods Randomised, placebo-controlled, double-blind study with 3 arms (1 control arm and 2 treatment arms).
Intention to treat
Randomisation method: continuous random numbers assigned to blinded study drugs or vehicle by
Biometric department. Blind
Accrual period: Aug. 89-Jan.94
Participants Eligibility criteria: non infected trauma pts, age>18yrs, expected ventilation for at least 2 days, expected
ICU stay for at least 3 days, ISS>16 and <74, inclusion within 24 hrs of admission
Exclusion criteria: isolated brain injury, prior antibiotic treatment, history of infection
Patients enrolled in the study: 357 (only two groups of patients, group A and C, are considered in this
comparison, totalling 267 pts)
ICU length of stay, mean: 20 days
Type of admission diagnosis: trauma=100%
treatment 1=2% treatment 2=2% CTR=6%
Stress ulcer prophylaxis applied: free
Interventions Group A, Treatment 1:

-Polymyxin E 100mg, Tobramycin 80mg, Amphotericin B 500mg applied orally and enterally 4 times a
day during the ICU stay
-Ciprofloxacin 200 mg x 2 iv, for 4 days
Group C, CTR:
- Placebo
- Ciprofloxacin 200 mg x 2 iv, for 4 days

concomitant occurence of purulent sputum, positive cultures of bronchial secretions and deterioration of
lung function
Mortality: in ICU
Notes This 3 arms study has been splitted in two comparisons; the control group C has been used twice:
comparison Lingnau a (group A vs group C)
comparison Lingnau b (group B vs group C)
Risk of bias
Lingnau 1997b
Methods see Lingnau a
Participants see Lingnau a

Only two groups of patients, group B and C, are considered in this comparison, totalling 267 patients
Interventions Group B, Treatment 2:

-Polymyxin E 100mg, Ciprofloxacin 50mg, Amphotericin B 500mg applied orally and enterally 4 times
a day during the ICU stay
-Ciprofloxacin 200 mg x 2 iv, for 4 days
Group C, CTR:
- Placebo
- Ciprofloxacin 200 mg x 2 iv, for 4 days
Outcomes see Lingnau a
Notes see Lingnau a
Risk of bias
Palomar 1992
Methods
Participants
Interventions
Outcomes
Notes
Risk of bias
Palomar 1997
Methods Randomised, multicentric (10 ICUs) study with 3 arms (1 treatment arm and 2 control arms; one control
arm was excluded from metanalysis because it was the only one receiving sucralfate)
Accrual period: Jul 89-Aug 91
Participants Eligibility criteria: patients requiring mechanical ventilation for more than 4 days, not infected at the time
of entry and not receiving antibiotic therapy
Exclusion criteria: ARDS, leukopenia, pregnancy
Length of stay in ICU, median 10 days
Type of admission diagnosis: medical 40% surgical 10% trauma 50%
Stress ulcer prophylaxis applied: sucralfate to one control group (excluded from metanalysis), antiacids or
H2-blockers to the two other groups
Interventions Group A, CTR 1:

-No prophylaxis
Group B, Treatment:
-Polymyxin E+B 100mg, Tobramycin 80mg, Amphotericin B 500 mg applied enterally and, as a 2%
paste, to the oropharynx 4 times a day until extubation
Group C*, CTR 2:
-Sucralfate
* This group was excluded from analysis because it was the only one receiving sucralfate
Outcomes Respiratory infections (acquired infections)

Diagnosis of pneumonia was based on the CDC criteria of 1980 (clinical or radiologic suspicion with:
purulent sputum, organism isolated from blood culture, isolation of pathogen from tracheal aspirate,
brush or biopsy. Bacteriologic evaluation was performed with brush or BAL in 50% of patients)
Diagnosis of trachobronchitis was based on the CDC criteria of 1980
Mortality: in ICU
Notes Personal contact with the main investigator provided data about 16 patients who were excluded from
thepublished paper (7 early extubation, 5 early death, 3 protocol violation, 1 other); these data are
Risk of bias
Palomar 1997 (Continued)
Pneumatikos 2002
Methods Randomised, placebo-controlled

Randomisation method: not stated
Participants Elegibility criteria: patients with multiple trauma admitted to the intensive care unit who required intu-
bation and had an expected time for mechanical ventilation exceeding 5 days.
Absence of cardiopulmonary disease, negative chest radiography, and a PaO2/FIO2 ratio higher than 300
mmHg
ICU length of stay, median:
Treatment=16 days
Control=23 days
Type of admission daignosis:
trauma=100%
Severity score on admission: APACHE II
treatment=18.1
control=19.1
Percentage of immunocompromised patients: not stated
Percentage of patients treated with systemic antibiotic therapy:
not stated
Stress ulcer prophylaxis applied: H2 blockers or sucralfate
Treatment=26%
Control=19%
Interventions Group A, treatment:

Polymyxin 73mg,
Tobramycin 73 mg, amphotericin 500 ml in 500 ml 0.9 saline solution at an infusion rate of 2 ml/h in
the subglottic area for the entire period of the study
Group B CTR:
placebo
Outcomes Ventilator associated pneumonia (VAP) defined as presence of new and persistent pulmonary infiltrates
in addition to two of the following criteria: body temperature>38.3 °C, leukocytes/mmˆ3) or leukopenia
(<4000 leukocytes/mmˆ3) and purulent tracheal secretions. The diagnosis of VAP was confirmed by
quantitative cultures.
Mortality: not specified
Notes
Risk of bias
Pneumatikos 2002 (Continued)
Pugin 1991

Accrual period: Apr 89-Nov 89
Participants Eligibility criteria: all adult patients admitted to the surgical ICU, at high risk of developing pneumonia
and intubated for more than 48 hrs
Exclusion criteria: organ transplantation
Length of stay in ICU, mean 13.8 days
Type of admission diagnosis: medical 11% surgical scheduled 11% surgical unscheduled 22% trauma
56%
Stress ulcer prophylaxis applied: sucralfate (61%), ranitidine (11%)

-Polymyxin B Sulfate 150mg, Neomycin Sulfate 1g, Vancomycin Hydrochloride 1g applied as a solution
to the retropharynx 6 times a day within 24 hrs after intubation until extubation or death
Group B, CTR:
-Placebo
Withdrawal from the study was possible at any time if the treating physicians estimated that there was
any problem related to administration of the drugs or side effects
Outcomes Respiratory infections (pneumonia acquired after 48 hrs): Pneumonia are defined by the “clinical pul-
monary infections score” (CPIS) greater or equal to 7 during the course of intubation and that remained
elevated (=7) for at least 3 days (i.e. for two consecutive measurements)
Notes Personal contact with the main investigator provided data about 27 patients who were excluded from
thepublished paper (20 early extubation, 7 early death); these data are considered in the analysis
Risk of bias
Quinio 1995
Methods Randomised, placebo-controlled, double-blind study. Intention to treat

Randomisation method: randomisation made by the Pharmacy’s Service according to computer generated
random numbers. Blind
Accrual period: Jan 91-Jan 93
Participants Eligibility criteria: trauma patients intubated within 24 hrs and ventilated for more than 48 hrs, ICU stay
>5 days and decontamination for more than 4 days
Exclusion criteria: age <16 yrs, antibiotic treatment in the week precedent to ICU admission, pregnancy
Length of stay in ICU, mean=20.5 days
Type of admission diagnosis: medical 2% trauma 98%
Severity score on admission: SAPS mean=11.2, ISS mean=31.3
GCS mean 6.5
Stress ulcer prophylaxis applied: sucralfate until enteral feeding was effective, H2-blockers in high risk
patients

-Polymyxin E 100 mg, Gentamycin 80mg, Amphotericin B 500mg applied enterally and in the nares
and, as a 2% paste, to the oropharynx 4 times a day until extubation or starting of enteral nutrition
Group B, CTR:
-Placebo
Outcomes Respiratory infections (pneumonia acquired after 48 hrs): Diagnosis of infection was based on:
purulent tracheal aspirate, fever >38.5°C, leukocytosis >10,000 WBC/mm3, new and persistent infiltrate
on chest X-ray
Mortality: in ICU
Notes
Risk of bias
Rocha 1992

Randomisation method: made by the Pharmacy’s service according to computer generated random num-
bers. Blind
Accrual period: Sept 89-Oct 90
Participants Eligibility criteria: expected mechanical ventilation for more than 3 days, stay in ICU more than 5 days
Exclusion criteria: infection or strong suspicion of this at the start of ventilation, antibiotic treatment in
the previous 7 days, neutropenia (WBC<500/mm3) and fever, pregnancy, history of hypersensitivity to
the topical agents
Type of admission diagnosis: medical 28% surgical scheduled 3% surgical unscheduled 1% trauma 68%
Severity score on admission: APACHE II mean=16.3, ISS not available, GCS mean=9
Percentage of immunocompromised patients: 0,7%
Stress ulcer prophylaxis applied: H2-blockers and antiacids

-Polymyxin E 100mg, Tobramycin 80mg, Amphotericin B 500 mg applied enterally and, as a 2% paste,
-Cefotaxime 6g/day iv for the first 4 days
Group B, CTR:
-Placebo
-No systemic prophylaxis

purulent pulmonary secretions, new infiltrates in the chest X-ray and one of the following:
fever/hypothermia, leukocytosis/leukopenia, positive physical examination, drop in arterial partial oxygen
pressure. Bacteriologic diagnosis, even if performed (with brush in few patients), was not essential
Mortality: in ICU
Notes Personal contact with the main investigator provided mortality data about 50 patients who were excluded
from the published paper (15 early extubation, 31 early death, 2 protocol violation, 2 other); these data
are considered in the analysis. Data about respiratory infections in excluded patients are not available
Risk of bias
Rodriguez-Rolda 1990
Methods Randomised, placebo-controlled, double-blind, dual-center study

Randomisation method: odd and even numbers. Open
Accrual period: Jun 88-Dec 88
Participants Eligibility criteria: patients intubated an mechanically ventilated for more than 72 hrs
Exclusion criteria: patients whose chest X-rays was difficult to interpret, with suspected inflammatory
images during the first 72 hrs, patients ventilated for less time
Length of stay in ICU, median 13.5 days
Stress ulcer prophylaxis applied: sucralfate or alkaline agents plus ranitidine according to a randomised
open protocol

-Polymyxin E, Tobramicin or Netilmicin, Amphotericin B and antiseptic applied enterally and, as a 2%
paste, to the oropharynx 4 times a day
-Antiseptic
Group B, CTR:
-Placebo
-Antiseptic
Outcomes Respiratory infections (pneumonia acquired after 72 hrs): Diagnosis of infection was based on the presence
of at least one in each category of criteria:
A) Clinical criteria: temperature >38°C, purulent bronchorrea, leukocytosis>15,000 WBC/mm3, in-
creased alveolar-arterial oxygen gradient;
B) Radiologic criteria: new and persistent infiltrate;
C) Bacteriologic criteria: quantitative culture of tracheal aspirates > 10ˆ3 CFU/ml (in 6 patients either
bronchoscopy or a telescoped catheter were used to obtain the sample)
Mortality: in ICU
published paper (2 early death, 1 other); these data are considered in the analysis
Risk of bias
Sanchez-Garcia 1992
Methods Randomised, placebo-controlled, double-blind, multicentric (5 ICUs) study

Accrual period: not available
Participants Eligibility criteria: expected ventilation for longer than 48 hrs, age >16 yrs
Exclusion criteria: death or extubation before 48 hrs, pregnancy, allergy to study antibiotics, organ trans-
plantation, absence or contraindication to nasogastric tube
Stress ulcer prophylaxis applied: each group was randomised to receive either sucralfate or H2-blockers

-Polymyxin E 100mg, Gentamycin 80mg, Amphotericin B 500 mg applied orally and enterally 4 times
a day until extubation
-Ceftriaxone 2g/day iv x3 days to uninfected patients
Group B, CTR:
- Placebo
-Systemic placebo to uninfected patients
Outcomes Respiratory infections (early and late acquired pneumonia):

new and persistent infiltrate on chest X-ray and 3 of the following: temperature >38.5°C, leukocytosis
>12,000 WBC/mm3 or leukopenia <3,000 WBC/mm3, purulent tracheal aspirate with growth of a
potentially pathogenic micro-organism
Mortality: in ICU
published paper (12 early extubation, 12 early death, 17 protocol violation, 2 transferring, 2 other); these
data are considered in the analysis
Risk of bias
Stoutenbeek 1996

Randomisation method: closed envelope method (the code was known by the pharmacist only). Blind
Accrual period: Nov 84 - Aug 86
Participants Eligibility criteria: all patients admitted to the surgical ICU with blunt trauma and an HTI-ISS >18, age
>18 yrs
Exclusion criteria: patients mechanically ventilated for less than 5 days or discharged from ICU within 7
days and with an HTI-ISS <18 after 24 hrs
Length of stay in ICU, mean=15 days
Severity score on admission: APACHE II mean=10.6, HTI-ISS mean=35.1
Stress ulcer prophylaxis applied: none except for patients with history of preexisting ulcer or on H2-
blockers

-Polymyxin E 100mg, Tobramycin 80mg, Amphotericin 500 mg applied enterally and, as a 2% paste, to
the oropharynx 4 times a day until ICU discharge
-Cefotaxime 50-100mg/kg/day iv for the first 5 days
Group B, CTR:
-Placebo
-Cefotaxime 50-100mg/kg/day iv for the first 5 days
The blinded medication was discontinued and topical prophylaxis was started when a patient developed
MOSF not responding to conventional therapy. The code was not broken and the patient was further
evaluated
Outcomes Respiratory infections (tracheobronchitis and pneumonia - early and late infections)
Diagnosis of infection was based on clinical criteria: temperature >38.5°C, WBC >12,5x10ˆ9/l or leukope-
nia <4x10ˆ9/l, purulent secretions or X-ray changes and significant growth of bacteria
Mortality: in ICU
Notes Data about 32 patients who were initially excluded (25 early extubation, 4 early death, 3 other) are
Risk of bias
Stoutenbeek 2
Methods Randomised, multicenter study. Intention to treat

Randomisation method: randomisation lists prepared by the Biometrical Department and supplied with
sealed envelopes. Blind
Accrual period: Oct 91-Jun 94
Participants Eligibility criteria: patients admitted within 24 hrs after a blunt trauma with an HTI-ISS >=16, necessi-
tating mechanical ventilation, age > 18 yrs
Exclusion criteria: previous antibiotic use for more than 3 days at study entry, allergy to cefotaxime,
referred patients from other hospital or secondary admissions with trauma occurred > 24 hrs before
Number of patients enrolled in the study: 405, but 402 pts were analysed
Length of stay in ICU, median=11 days
Severity score on admission: APACHE II mean=12.6, HTI-ISS mean=35.0
Stress ulcer prophylaxis applied: sucralfate, H2-blockers, antiacids; sucralfate was not allowed in the
treatment group

-Polymyxin E, Tobramycin, Amphotericin B applied orally, enterally and vaginally 4 times a day until
discharge
Group B, CTR:
-Standard antibiotic prophylaxis (no fluoroquinolones)
Outcomes Respiratory infections (pneumonia and tracheobronchitis, primary and acquired)

Diagnosis of pneumonia was based on any of the following: presence of a new and progressive pulmonary
infiltrate on chest X-ray for >=48 hrs, purulent sputum, fever >38.5°C, leukocytosis >12,000/ml or
leukopenia <4000/ml. A fiberoptic guide protected brush specimen or BAL was recommended
Diagnosis of tracheobronchitis was based on any of the following: purulent sputum on Gram stain, fever
>38.5°C, leukocytes >12000 or 4000/ml
Mortality: at follow up (2 weeks after discharge to the wards)
Notes Data on 3 patients (protocol violation) are not available. Mortality datum about one more patient is
lacking.
Risk of bias
Ulrich 1989
Methods Randomised, placebo-controlled study

Randomisation method: sealed envelopes containing a random code for clusters of 4 patients. Blind
Accrual period: Oct 86-Sep 87
Participants Eligibility criteria: patients expected to stay in the ICU more than 5 days and ventilated more than 48 hrs
Exclusion criteria: pts who died within 24 hrs after randomisation
Percentage of ventilated patients: about 80%
Length of stay in ICU, median=10 days
16%
Severity score on admission: SAPS mean=11.7, ISS mean=36.9

-Polymyxin E 100mg, Norfloxacin 50mg, Amphotericin B 500 mg, applied enterally and, as a 2% paste,
-Trimethoprim 500mg iv
Group B, CTR:
-Placebo

Diagnosis of infection was based on clinical and radiologic signs of pulmonary infiltrations with fever and
leukocytosis and a dense growth in cultures of sputum of tracheal aspirate
Mortality: in ICU
published paper (early death); these data are considered in the analysis
Risk of bias
Unertl 1987
Methods Randomised study, blinded for radiologic diagnosis

Randomisation method: blocked randomisation scheme and the sealed envelope technique. Blind
Accrual period: May 84 - Jan 85
Unertl 1987 (Continued)
Participants Eligibility criteria: all patients admitted to the ICU with: intubation within 24 hrs after the onset of an
acute disease or surgery, expected ventilation > 6 days, interval between intubation and first microbiologic
culture < 36 hrs
Exclusion criteria: Patients with infection, systemic antibiotic treatment, respiratory distress syndrome,
leucopenia and myelosuppression on admission, renal failure
Length of stay in ICU: not available
Type of admission diagnosis: medical 52%, surgical 15%,trauma 33%
Severity score on admission: SAPS mean=12.5, GCS (75% of patients have GCS <7)
days: not available
Stress ulcer prophylaxis applied: H2-blockers to all patients and antiacids if pH <4

-Polymyxin B 50mg, Gentamycin 80mg, applied orally, nasally and enterally 4 times a day until extubation
-Amphoterycin B 300mg applied orally 4 times a day
Group B, CTR:
-No prophylaxis

new ’definite’ infiltrate on chest X-ray together with increasing amounts of purulent tracheobronchial
secretion containing >3x10ˆ4 granulocytes/mcl and at least 2 of the following: new febrile spikes >38.5°C,
blood leukocyte count >12000/mcl or <4000/mcl, decrease of PaO2 requiring an increase of the FiO2 of
at least 15% to mantain oxygen tension.
’Definite’ is an infiltrate confirmed by 2 blind indipendent radiologists and not reversible after chest
physiotherapy
Mortality: in ICU
Notes
Risk of bias
Verwaest 1997
Methods Randomised study with 3 arms (1 control arm and 2 treatment arms)
Randomisation method: sealed envelopes with computer generated random numbers. Blind
Accrual period: Sept 89-Mar 91
Participants Eligibility criteria: expected ventilation > 48 hrs

Exclusion criteria: age<18 yrs, pregnancy, recent organ transplantation, serious granulocytopenia(<=500
WBC/mm3), ventilation <48 hrs, death before 48 hrs, missing of essential data in the clinical or bacteri-
ological dossier
Number of patients enrolled in the study: 660 (only two groups of pts, A and B, are considered in this
comparison, totalling 440 pts)
Length of stay in ICU, mean=19.6 days
Type of admission diagnosis: medical 10%, surgical 67% trauma 23%
days: treatment 1=34% treatment 2=31% CTR=34%
Stress ulcer prophylaxis applied: sucralfate 2g x4

- No prophylaxis, antibiotic therapy was used only if an infection was suspected
Group B, Treatment 1:
- Ofloxacin 200mgx2, Amphoterycin B 500mg x4 applied enterally and, as a 2% paste, to the oropharynx
4 times a day until discharge
- Ofloxacin 200mg iv x 4 days
Outcomes Respiratory infections (pneumonia acquired after 48 hrs):

Fever >38.5°C, leukocytosis >10,000 cells/mcl, luxuriant growth of potentially pathogenic micro-organ-
isms in culture of bronchial aspirate, new and persistent infiltrate on chest X-ray
Mortality: in ICU
Notes This 3 arms study has been splitted in two comparison, the control group A has been used twice:
comparison Verwaest a (group A vs group B)
comparison Verwaest b (group A vs group C)
Personal contact with the main investigator provided mortality data about 82 patients who were excluded
(33 early death, 49 other); these data are considered in the analysis.Data about respiratory infections in
excluded patients are not available
Risk of bias
Wiener 1995

Randomisation method: random number table in blocks of six patients. Open
Accrual period: 8 months
Participants Eligibility criteria: expected intubation for more than 48 hrs, inclusion within 18 hrs of intubation,
age>18yrs
Exclusion criteria: refusal to consent, allergy to one of the components of the regimen, active inflammatory
bowel disease
Patients enrolled in the study: 121, but 60 pts were excluded leaving 61 pts for analysis
Length of stay in ICU, mean: 11.3 days
Type of admission diagnosis: not available
Percentage of immunocompromised patients: >5%
Stress ulcer prophylaxis applied: H2-blockers to most pts

-Polymyxin E 100mg, Gentamycin 80mg, Nystatin 2,000,000 UI applied enterally 4 times a day and, as
a 2% paste, to the oropharynx until extubation or tracheostomy
Group B, CTR:
-Placebo
Outcomes Respiratory infections (pneumonia acquired after 48 hrs):

Diagnosis of infection was based on the presence of the following: persistence of a new or progressive
infiltrate on chest-film, fever >38.5°C and/or leukocytosis >12,000/mm3, growth of > 10ˆ3 bacteria from
a quantitative culture of lower respiratory tract secretions obtained with a blind protected catheter
Mortality: in ICU
Notes 60 patients were excluded after randomisation; data are not available
Risk of bias
Winter 1992

Randomisation method: sealed envelopes based on a computer generated table of random numbers. Blind
Accrual period: Jul 88-May 90
Winter 1992 (Continued)
Participants Eligibility criteria: patients likely to remain in the ICU for at least 48 hrs
Exclusion criteria: allergy to the antibiotics used, age >85yrs, pregnancy
Length of stay in ICU, median= 4 days
13%
Severity score on admission: APACHE II mean=15.3, ISS mean= 26.2
Stress ulcer prophylaxis applied: all CTR patients received sucralfate; H2-blockers were used in patients
of both groups with peptic ulcer or pancreatitis
Interventions Group B, CTR:

-Conventional infections treatment and prophylaxis
Group C, Treatment:
-Polymyxin E 100mg, Tobramycin 80mg, Amphotericin B 500 mg applied enterally and, as a 2% gel, to
the oropharynx 4 times a day
-Ceftazidime 50mg/kg/day iv x 3 days
Outcomes Respiratory infections (pneumonia acquired after 48 hrs): Diagnosis of infection was based on:
temperature >38.5°C two times in 24 hrs, WBC<4 or >12x10ˆ9/l, positive BAL, two of the following:
new pulmonary infiltrates on chest X-ray, purulent sputum, increase of 15% in FiO2 to maintain previous
oxygenation
Notes Few patients were excluded after randomisation; data are not available
Risk of bias
APACHE Acute Physiology and Chronic Health Evaluation

ARDS Acute Respiratory Distress Syndrome
BAL Broncho-Alveolar-Lavage
CCU Coronary Care Unit
CDC Centre for Disease Control
CFU Colony Forming Unit
CI Confidence Interval
CTR Control group
GCS Glasgow Coma Score
hrs hours
HTI-ISS Hospital Trauma Index-Injury Severity Score
ICU Intensive Care Unit
ISS Injury Severity Score
iv intravenous
MOSF Multi-Organ-System-Failure
OR Odds Ratio
pts patients
RCTs Randomised Controlled Trials
RD Risk Differences
RR Relative Risk
RTIs Respiratory Tract Infections
SAPS Symplified Acute Physiology Score
SDD Selective Decontamination of the Digestive Tract
VAP Ventilator Associated Pneumonia
VO2 Oxygen Consumption
yrs years
WBC White Blood Count
Characteristics of excluded studies [ordered by study ID]
Barret 2001 The study included only pediatric burned patients
Bion 1994 The study included a selected population of patients undergoing liver transplant
Bouter 2002 The study included only patients undergoing cardiopulmonary by-pass
Flaherty 1990 The study included a selected population of cardiosurgical patients
Garbino 2002 The study tested the effectiveness of fluconazole as both groups received SDD
Hellinger 2002 The study included only liver transplant patients
Hunefeld 1989 After contacting the principal investigator it become apparent that it was not a randomised study
Lipman 1994 After contacting the principal investigator it become apparent that it was not a randomised study
Luiten 1995 The study included a selected population of patients affected by pancreatitis characterised by a low percentage
of ICU admissions.
Martinez 1994 The study compared the effect of two different prophylactic regimens without a control group
Martinez-Pellus 1993 The study included a selected population of cardiosurgical patients
Nardi 2001 The study tested the effectiveness of mupirocin as both groups received SDD
Rayes 2002 The study included only liver transplant patients
Rolando 1996 The study included a selected population of patients with acute hepatic failure
(Continued)
Schardey 1994 The study included a selected population of patients undergoing gastric surgery and characterised by a low
percentage of ICU admission.
Tetteroo 1990 The study included a selected population of patients undergoing oesophageal resection and characterised by
a short length of stay in ICU.
Zwaveling 2002 The study included only liver transplant patients
Characteristics of ongoing studies [ordered by study ID]
Anonymous
Trial name or title Surviaval benefit in severely burned patients receiving selective decontamination of the digestive tract: a
randomized placebo controlled double blind trial
Methods
Participants 117 adult burn patients admitted in a 6 bed ICU burn unit
Interventions Topical plus systemic (cefotaxime) SDD vs no treatment
Outcomes Mortality, infection
Starting date May 1997
Contact information Rick Van Saene
Notes Unpublished manuscript provided by Rick Van Seane
DATA AND ANALYSES
Comparison 1. topical plus systemic vs no prophylaxis
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 overall mortality 17 4075 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.75 [0.65, 0.87]
2 mortality according to 17 Peto Odds Ratio (Peto, Fixed, 95% CI) Subtotals only
randomisation
2.1 blind randomisation 14 3364 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.77 [0.66, 0.90]
2.2 open randomisation 3 711 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.68 [0.48, 0.97]
3 mortality according to blinding 17 Peto Odds Ratio (Peto, Fixed, 95% CI) Subtotals only
of the studies
3.1 double-blind 4 1013 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.63 [0.48, 0.83]
3.2 unblind 13 3062 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.80 [0.68, 0.95]
4 RTIs 15 2498 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.32 [0.26, 0.38]
5 RTIs according to randomisation 15 Peto Odds Ratio (Peto, Fixed, 95% CI) Subtotals only
6 RTIs according to blinding of 15 Peto Odds Ratio (Peto, Fixed, 95% CI) Subtotals only
the studies
Comparison 2. topical vs control
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 overall mortality 20 2830 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.97 [0.81, 1.16]
1.1 topical plus systemic vs 7 1233 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.98 [0.73, 1.32]
systemic
1.2 topical vs no prophylaxis 13 1597 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.96 [0.78, 1.20]
2 mortality according to 20 Peto Odds Ratio (Peto, Fixed, 95% CI) Subtotals only
randomisation
3 mortality according to blinding 20 Peto Odds Ratio (Peto, Fixed, 95% CI) Subtotals only
of the studies
4 RTIs 18 2664 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.52 [0.43, 0.63]
4.1 topical plus systemic vs 6 1115 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.81 [0.61, 1.08]
systemic
4.2 topical vs no prophylaxis 12 1549 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.37 [0.29, 0.48]
5 RTIs according to randomisation 18 Peto Odds Ratio (Peto, Fixed, 95% CI) Subtotals only
6 RTIs according to blinding of 18 Peto Odds Ratio (Peto, Fixed, 95% CI) Subtotals only
the studies
Analysis 1.1. Comparison 1 topical plus systemic vs no prophylaxis, Outcome 1 overall mortality.
Review: Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care
Comparison: 1 topical plus systemic vs no prophylaxis
Outcome: 1 overall mortality
Study or subgroup Control Peto Odds Ratio Weight Peto Odds Ratio
n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI
Abele-Horn 1997 11/58 5/30 1.5 % 1.17 [ 0.37, 3.63 ]
Aerdts 1991 4/28 12/60 1.5 % 0.68 [ 0.22, 2.17 ]
Blair 1991 24/161 32/170 6.0 % 0.76 [ 0.43, 1.34 ]
Boland 1991 2/32 4/32 0.7 % 0.48 [ 0.09, 2.57 ]
Cockerill 1992 11/75 16/75 2.9 % 0.64 [ 0.28, 1.46 ]
de Jonge 2003 113/466 146/468 24.3 % 0.71 [ 0.53, 0.94 ]
Finch 1991 15/24 10/25 1.6 % 2.42 [ 0.80, 7.32 ]
Jacobs 1992 14/45 23/46 2.9 % 0.46 [ 0.20, 1.06 ]
Kerver 1988 14/49 15/47 2.7 % 0.85 [ 0.36, 2.03 ]
Lenhart 1994 52/265 75/262 12.5 % 0.61 [ 0.41, 0.91 ]
Palomar 1997 14/50 14/49 2.6 % 0.97 [ 0.41, 2.32 ]
Rocha 1992 27/74 40/77 4.9 % 0.54 [ 0.28, 1.02 ]
Sanchez-Garcia 1992 51/131 65/140 8.6 % 0.74 [ 0.46, 1.19 ]
Stoutenbeek 2 42/201 44/200 8.8 % 0.94 [ 0.58, 1.51 ]
Ulrich 1989 22/55 33/57 3.7 % 0.49 [ 0.24, 1.03 ]
Verwaest 1997 47/220 40/220 9.1 % 1.22 [ 0.76, 1.95 ]
Winter 1992 33/91 40/92 5.7 % 0.74 [ 0.41, 1.34 ]
Total (95% CI) 2025 2050 100.0 % 0.75 [ 0.65, 0.87 ]

Total events: 496 (), 614 (Control)
Heterogeneity: Chi2 = 15.50, df = 16 (P = 0.49); I2 =0.0%
Test for overall effect: Z = 3.94 (P = 0.000080)
0.1 0.2 0.5 1.0 2.0 5.0 10.0
Analysis 1.2. Comparison 1 topical plus systemic vs no prophylaxis, Outcome 2 mortality according to
randomisation.
Outcome: 2 mortality according to randomisation
1 blind randomisation
Aerdts 1991 4/28 12/60 1.8 % 0.68 [ 0.22, 2.17 ]
Blair 1991 24/161 32/170 7.3 % 0.76 [ 0.43, 1.34 ]
Boland 1991 2/32 4/32 0.9 % 0.48 [ 0.09, 2.57 ]
Cockerill 1992 11/75 16/75 3.5 % 0.64 [ 0.28, 1.46 ]
de Jonge 2003 113/466 146/468 29.2 % 0.71 [ 0.53, 0.94 ]
Finch 1991 15/24 10/25 1.9 % 2.42 [ 0.80, 7.32 ]
Jacobs 1992 14/45 23/46 3.5 % 0.46 [ 0.20, 1.06 ]
Palomar 1997 14/50 14/49 3.2 % 0.97 [ 0.41, 2.32 ]
Rocha 1992 27/74 40/77 5.8 % 0.54 [ 0.28, 1.02 ]
Sanchez-Garcia 1992 51/131 65/140 10.4 % 0.74 [ 0.46, 1.19 ]
Stoutenbeek 2 42/201 44/200 10.5 % 0.94 [ 0.58, 1.51 ]
Ulrich 1989 22/55 33/57 4.4 % 0.49 [ 0.24, 1.03 ]
Verwaest 1997 47/220 40/220 10.9 % 1.22 [ 0.76, 1.95 ]
Winter 1992 33/91 40/92 6.9 % 0.74 [ 0.41, 1.34 ]
Subtotal (95% CI) 1653 1711 100.0 % 0.77 [ 0.66, 0.90 ]

Heterogeneity: Chi2 = 13.75, df = 13 (P = 0.39); I2 =5%
2 open randomisation
Abele-Horn 1997 11/58 5/30 9.2 % 1.17 [ 0.37, 3.63 ]
Kerver 1988 14/49 15/47 15.9 % 0.85 [ 0.36, 2.03 ]
Lenhart 1994 52/265 75/262 74.9 % 0.61 [ 0.41, 0.91 ]
Subtotal (95% CI) 372 339 100.0 % 0.68 [ 0.48, 0.97 ]

Test for subgroup differences: Chi2 = 0.35, df = 1 (P = 0.56), I2 =0.0%
0.1 0.2 0.5 1.0 2.0 5.0 10.0
Aerdts 1991 4/28 12/60 1.8 % 0.68 [ 0.22, 2.17 ]
Blair 1991 24/161 32/170 7.3 % 0.76 [ 0.43, 1.34 ]
Boland 1991 2/32 4/32 0.9 % 0.48 [ 0.09, 2.57 ]
Cockerill 1992 11/75 16/75 3.5 % 0.64 [ 0.28, 1.46 ]
de Jonge 2003 113/466 146/468 29.2 % 0.71 [ 0.53, 0.94 ]
Finch 1991 15/24 10/25 1.9 % 2.42 [ 0.80, 7.32 ]
Jacobs 1992 14/45 23/46 3.5 % 0.46 [ 0.20, 1.06 ]
Palomar 1997 14/50 14/49 3.2 % 0.97 [ 0.41, 2.32 ]
Rocha 1992 27/74 40/77 5.8 % 0.54 [ 0.28, 1.02 ]
Sanchez-Garcia 1992 51/131 65/140 10.4 % 0.74 [ 0.46, 1.19 ]
Stoutenbeek 2 42/201 44/200 10.5 % 0.94 [ 0.58, 1.51 ]
Ulrich 1989 22/55 33/57 4.4 % 0.49 [ 0.24, 1.03 ]
Verwaest 1997 47/220 40/220 10.9 % 1.22 [ 0.76, 1.95 ]
Winter 1992 33/91 40/92 6.9 % 0.74 [ 0.41, 1.34 ]
Subtotal (95% CI) 1653 1711 100.0 % 0.77 [ 0.66, 0.90 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Abele-Horn 1997 11/58 5/30 9.2 % 1.17 [ 0.37, 3.63 ]
Kerver 1988 14/49 15/47 15.9 % 0.85 [ 0.36, 2.03 ]
Lenhart 1994 52/265 75/262 74.9 % 0.61 [ 0.41, 0.91 ]
Subtotal (95% CI) 372 339 100.0 % 0.68 [ 0.48, 0.97 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Analysis 1.3. Comparison 1 topical plus systemic vs no prophylaxis, Outcome 3 mortality according to
blinding of the studies.
Outcome: 3 mortality according to blinding of the studies
1 double-blind
Boland 1991 2/32 4/32 2.7 % 0.48 [ 0.09, 2.57 ]
Lenhart 1994 52/265 75/262 46.9 % 0.61 [ 0.41, 0.91 ]
Rocha 1992 27/74 40/77 18.2 % 0.54 [ 0.28, 1.02 ]
Sanchez-Garcia 1992 51/131 65/140 32.3 % 0.74 [ 0.46, 1.19 ]
Subtotal (95% CI) 502 511 100.0 % 0.63 [ 0.48, 0.83 ]

2 unblind
Abele-Horn 1997 11/58 5/30 2.1 % 1.17 [ 0.37, 3.63 ]
0.1 0.2 0.5 1.0 2.0 5.0 10.0

(Continued . . . )
(. . . Continued)
Aerdts 1991 4/28 12/60 2.0 % 0.68 [ 0.22, 2.17 ]
Blair 1991 24/161 32/170 8.3 % 0.76 [ 0.43, 1.34 ]
Cockerill 1992 11/75 16/75 3.9 % 0.64 [ 0.28, 1.46 ]
de Jonge 2003 113/466 146/468 33.2 % 0.71 [ 0.53, 0.94 ]
Finch 1991 15/24 10/25 2.2 % 2.42 [ 0.80, 7.32 ]
Jacobs 1992 14/45 23/46 3.9 % 0.46 [ 0.20, 1.06 ]
Kerver 1988 14/49 15/47 3.6 % 0.85 [ 0.36, 2.03 ]
Palomar 1997 14/50 14/49 3.6 % 0.97 [ 0.41, 2.32 ]
Stoutenbeek 2 42/201 44/200 12.0 % 0.94 [ 0.58, 1.51 ]
Ulrich 1989 22/55 33/57 5.0 % 0.49 [ 0.24, 1.03 ]
Verwaest 1997 47/220 40/220 12.4 % 1.22 [ 0.76, 1.95 ]
Winter 1992 33/91 40/92 7.8 % 0.74 [ 0.41, 1.34 ]
Subtotal (95% CI) 1523 1539 100.0 % 0.80 [ 0.68, 0.95 ]

Test for subgroup differences: Chi2 = 2.21, df = 1 (P = 0.14), I2 =55%
0.1 0.2 0.5 1.0 2.0 5.0 10.0
1 double-blind
Boland 1991 2/32 4/32 2.7 % 0.48 [ 0.09, 2.57 ]
Lenhart 1994 52/265 75/262 46.9 % 0.61 [ 0.41, 0.91 ]
Rocha 1992 27/74 40/77 18.2 % 0.54 [ 0.28, 1.02 ]
Sanchez-Garcia 1992 51/131 65/140 32.3 % 0.74 [ 0.46, 1.19 ]
Subtotal (95% CI) 502 511 100.0 % 0.63 [ 0.48, 0.83 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
2 unblind
Abele-Horn 1997 11/58 5/30 2.1 % 1.17 [ 0.37, 3.63 ]
Aerdts 1991 4/28 12/60 2.0 % 0.68 [ 0.22, 2.17 ]
Blair 1991 24/161 32/170 8.3 % 0.76 [ 0.43, 1.34 ]
Cockerill 1992 11/75 16/75 3.9 % 0.64 [ 0.28, 1.46 ]
de Jonge 2003 113/466 146/468 33.2 % 0.71 [ 0.53, 0.94 ]
Finch 1991 15/24 10/25 2.2 % 2.42 [ 0.80, 7.32 ]
Jacobs 1992 14/45 23/46 3.9 % 0.46 [ 0.20, 1.06 ]
Kerver 1988 14/49 15/47 3.6 % 0.85 [ 0.36, 2.03 ]
0.1 0.2 0.5 1.0 2.0 5.0 10.0

(Continued . . . )
(. . . Continued)
Palomar 1997 14/50 14/49 3.6 % 0.97 [ 0.41, 2.32 ]
Stoutenbeek 2 42/201 44/200 12.0 % 0.94 [ 0.58, 1.51 ]
Ulrich 1989 22/55 33/57 5.0 % 0.49 [ 0.24, 1.03 ]
Verwaest 1997 47/220 40/220 12.4 % 1.22 [ 0.76, 1.95 ]
Winter 1992 33/91 40/92 7.8 % 0.74 [ 0.41, 1.34 ]
Subtotal (95% CI) 1523 1539 100.0 % 0.80 [ 0.68, 0.95 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Analysis 1.4. Comparison 1 topical plus systemic vs no prophylaxis, Outcome 4 RTIs.
Outcome: 4 RTIs
Abele-Horn 1997 13/58 23/30 4.4 % 0.11 [ 0.04, 0.27 ]
Aerdts 1991 1/28 29/60 3.9 % 0.14 [ 0.05, 0.36 ]
Blair 1991 12/161 38/170 9.7 % 0.31 [ 0.17, 0.57 ]
Boland 1991 14/32 17/32 3.7 % 0.69 [ 0.26, 1.83 ]
Cockerill 1992 4/75 12/75 3.3 % 0.33 [ 0.12, 0.92 ]
Finch 1991 4/20 7/24 1.9 % 0.62 [ 0.16, 2.40 ]
Jacobs 1992 0/45 4/46 0.9 % 0.13 [ 0.02, 0.95 ]
Kerver 1988 5/49 31/47 5.2 % 0.09 [ 0.04, 0.22 ]
Palomar 1997 10/50 25/49 5.2 % 0.26 [ 0.11, 0.59 ]
Rocha 1992 7/47 25/54 5.0 % 0.24 [ 0.10, 0.55 ]
Sanchez-Garcia 1992 32/131 60/140 13.8 % 0.44 [ 0.27, 0.73 ]
Stoutenbeek 2 61/202 99/200 21.9 % 0.45 [ 0.30, 0.67 ]
0.1 0.2 0.5 1.0 2.0 5.0 10.0

(Continued . . . )
(. . . Continued)
Ulrich 1989 7/55 26/57 5.3 % 0.21 [ 0.09, 0.47 ]
Verwaest 1997 22/193 40/185 11.8 % 0.48 [ 0.28, 0.82 ]
Winter 1992 3/91 17/92 4.1 % 0.21 [ 0.08, 0.54 ]
Total (95% CI) 1237 1261 100.0 % 0.32 [ 0.26, 0.38 ]

Test for overall effect: Z = 12.07 (P < 0.00001)
0.1 0.2 0.5 1.0 2.0 5.0 10.0
Analysis 1.5. Comparison 1 topical plus systemic vs no prophylaxis, Outcome 5 RTIs according to
randomisation.
Outcome: 5 RTIs according to randomisation
Aerdts 1991 1/28 29/60 4.4 % 0.14 [ 0.05, 0.36 ]
Blair 1991 12/161 38/170 10.7 % 0.31 [ 0.17, 0.57 ]
Boland 1991 14/32 17/32 4.1 % 0.69 [ 0.26, 1.83 ]
Cockerill 1992 4/75 12/75 3.6 % 0.33 [ 0.12, 0.92 ]
Finch 1991 4/20 7/24 2.1 % 0.62 [ 0.16, 2.40 ]
Jacobs 1992 0/45 4/46 1.0 % 0.13 [ 0.02, 0.95 ]
Palomar 1997 10/50 25/49 5.7 % 0.26 [ 0.11, 0.59 ]
Rocha 1992 7/47 25/54 5.5 % 0.24 [ 0.10, 0.55 ]
Sanchez-Garcia 1992 32/131 60/140 15.3 % 0.44 [ 0.27, 0.73 ]
Stoutenbeek 2 61/202 99/200 24.2 % 0.45 [ 0.30, 0.67 ]
Ulrich 1989 7/55 26/57 5.9 % 0.21 [ 0.09, 0.47 ]
Verwaest 1997 22/193 40/185 13.0 % 0.48 [ 0.28, 0.82 ]
Winter 1992 3/91 17/92 4.5 % 0.21 [ 0.08, 0.54 ]
0.1 0.2 0.5 1.0 2.0 5.0 10.0

(Continued . . . )
(. . . Continued)
Subtotal (95% CI) 1130 1184 100.0 % 0.36 [ 0.29, 0.43 ]
Abele-Horn 1997 13/58 23/30 46.0 % 0.11 [ 0.04, 0.27 ]
Kerver 1988 5/49 31/47 54.0 % 0.09 [ 0.04, 0.22 ]
Subtotal (95% CI) 107 77 100.0 % 0.10 [ 0.06, 0.18 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Aerdts 1991 1/28 29/60 4.4 % 0.14 [ 0.05, 0.36 ]
Blair 1991 12/161 38/170 10.7 % 0.31 [ 0.17, 0.57 ]
Boland 1991 14/32 17/32 4.1 % 0.69 [ 0.26, 1.83 ]
Cockerill 1992 4/75 12/75 3.6 % 0.33 [ 0.12, 0.92 ]
Finch 1991 4/20 7/24 2.1 % 0.62 [ 0.16, 2.40 ]
Jacobs 1992 0/45 4/46 1.0 % 0.13 [ 0.02, 0.95 ]
Palomar 1997 10/50 25/49 5.7 % 0.26 [ 0.11, 0.59 ]
Rocha 1992 7/47 25/54 5.5 % 0.24 [ 0.10, 0.55 ]
Sanchez-Garcia 1992 32/131 60/140 15.3 % 0.44 [ 0.27, 0.73 ]
Stoutenbeek 2 61/202 99/200 24.2 % 0.45 [ 0.30, 0.67 ]
Ulrich 1989 7/55 26/57 5.9 % 0.21 [ 0.09, 0.47 ]
0.1 0.2 0.5 1.0 2.0 5.0 10.0

(Continued . . . )
(. . . Continued)
Verwaest 1997 22/193 40/185 13.0 % 0.48 [ 0.28, 0.82 ]
Winter 1992 3/91 17/92 4.5 % 0.21 [ 0.08, 0.54 ]
Subtotal (95% CI) 1130 1184 100.0 % 0.36 [ 0.29, 0.43 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Abele-Horn 1997 13/58 23/30 46.0 % 0.11 [ 0.04, 0.27 ]
Kerver 1988 5/49 31/47 54.0 % 0.09 [ 0.04, 0.22 ]
Subtotal (95% CI) 107 77 100.0 % 0.10 [ 0.06, 0.18 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Analysis 1.6. Comparison 1 topical plus systemic vs no prophylaxis, Outcome 6 RTIs according to blinding
of the studies.
Outcome: 6 RTIs according to blinding of the studies
1 double-blind
Boland 1991 14/32 17/32 16.4 % 0.69 [ 0.26, 1.83 ]
Rocha 1992 7/47 25/54 22.2 % 0.24 [ 0.10, 0.55 ]
Sanchez-Garcia 1992 32/131 60/140 61.5 % 0.44 [ 0.27, 0.73 ]
Subtotal (95% CI) 210 226 100.0 % 0.41 [ 0.28, 0.61 ]

2 unblind
Abele-Horn 1997 13/58 23/30 5.7 % 0.11 [ 0.04, 0.27 ]
Aerdts 1991 1/28 29/60 5.1 % 0.14 [ 0.05, 0.36 ]
Blair 1991 12/161 38/170 12.5 % 0.31 [ 0.17, 0.57 ]
Cockerill 1992 4/75 12/75 4.2 % 0.33 [ 0.12, 0.92 ]
Finch 1991 4/20 7/24 2.5 % 0.62 [ 0.16, 2.40 ]
Jacobs 1992 0/45 4/46 1.1 % 0.13 [ 0.02, 0.95 ]
Kerver 1988 5/49 31/47 6.7 % 0.09 [ 0.04, 0.22 ]
Palomar 1997 10/50 25/49 6.7 % 0.26 [ 0.11, 0.59 ]
Stoutenbeek 2 61/202 99/200 28.3 % 0.45 [ 0.30, 0.67 ]
Ulrich 1989 7/55 26/57 6.9 % 0.21 [ 0.09, 0.47 ]
Verwaest 1997 22/193 40/185 15.2 % 0.48 [ 0.28, 0.82 ]
Winter 1992 3/91 17/92 5.2 % 0.21 [ 0.08, 0.54 ]
Subtotal (95% CI) 1027 1035 100.0 % 0.29 [ 0.24, 0.36 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
1 double-blind
Boland 1991 14/32 17/32 16.4 % 0.69 [ 0.26, 1.83 ]
Rocha 1992 7/47 25/54 22.2 % 0.24 [ 0.10, 0.55 ]
Sanchez-Garcia 1992 32/131 60/140 61.5 % 0.44 [ 0.27, 0.73 ]
Subtotal (95% CI) 210 226 100.0 % 0.41 [ 0.28, 0.61 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
2 unblind
Abele-Horn 1997 13/58 23/30 5.7 % 0.11 [ 0.04, 0.27 ]
Aerdts 1991 1/28 29/60 5.1 % 0.14 [ 0.05, 0.36 ]
Blair 1991 12/161 38/170 12.5 % 0.31 [ 0.17, 0.57 ]
Cockerill 1992 4/75 12/75 4.2 % 0.33 [ 0.12, 0.92 ]
Finch 1991 4/20 7/24 2.5 % 0.62 [ 0.16, 2.40 ]
Jacobs 1992 0/45 4/46 1.1 % 0.13 [ 0.02, 0.95 ]
Kerver 1988 5/49 31/47 6.7 % 0.09 [ 0.04, 0.22 ]
Palomar 1997 10/50 25/49 6.7 % 0.26 [ 0.11, 0.59 ]
Stoutenbeek 2 61/202 99/200 28.3 % 0.45 [ 0.30, 0.67 ]
0.1 0.2 0.5 1.0 2.0 5.0 10.0

(Continued . . . )
(. . . Continued)
Ulrich 1989 7/55 26/57 6.9 % 0.21 [ 0.09, 0.47 ]
Verwaest 1997 22/193 40/185 15.2 % 0.48 [ 0.28, 0.82 ]
Winter 1992 3/91 17/92 5.2 % 0.21 [ 0.08, 0.54 ]
Subtotal (95% CI) 1027 1035 100.0 % 0.29 [ 0.24, 0.36 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Analysis 2.1. Comparison 2 topical vs control, Outcome 1 overall mortality.
Comparison: 2 topical vs control
1 topical plus systemic vs systemic

Ferrer 1992 15/51 14/50 4.2 % 1.07 [ 0.45, 2.52 ]
Gaussorgues 1991 29/59 29/59 6.0 % 1.00 [ 0.49, 2.05 ]
Hammond 1992 34/162 31/160 10.5 % 1.10 [ 0.64, 1.90 ]
Laggner 1994 9/33 14/34 3.1 % 0.54 [ 0.20, 1.48 ]
Lingnau 1997 9/90 17/177 4.3 % 1.05 [ 0.45, 2.46 ]
Lingnau 1997b 13/90 17/177 4.8 % 1.62 [ 0.73, 3.62 ]
Stoutenbeek 1996 2/49 8/42 1.8 % 0.22 [ 0.06, 0.82 ]
Subtotal (95% CI) 534 699 34.7 % 0.98 [ 0.73, 1.32 ]

2 topical vs no prophylaxis
Bergmans 2001 30/87 59/139 10.4 % 0.72 [ 0.42, 1.24 ]
Brun-Buisson 1989 14/65 15/68 4.6 % 0.97 [ 0.43, 2.20 ]
Cerra 1992 13/25 10/23 2.5 % 1.40 [ 0.46, 4.29 ]
0.1 0.2 0.5 1.0 2.0 5.0 10.0

(Continued . . . )
(. . . Continued)
Gastinne 1992 88/220 82/225 21.3 % 1.16 [ 0.79, 1.70 ]
Georges 1994 3/31 5/33 1.4 % 0.61 [ 0.14, 2.66 ]
Jacobs 2 unpublished 15/35 19/35 3.6 % 0.64 [ 0.25, 1.62 ]
Korinek 1993 22/96 17/95 6.3 % 1.36 [ 0.67, 2.74 ]
Pneumatikos 2002 5/31 7/30 2.0 % 0.64 [ 0.18, 2.23 ]
Pugin 1991 10/38 11/41 3.2 % 0.97 [ 0.36, 2.63 ]
Quinio 1995 12/76 10/73 3.8 % 1.18 [ 0.48, 2.91 ]
Rodriguez-Rolda 1990 5/14 7/17 1.5 % 0.80 [ 0.19, 3.34 ]
Unertl 1987 5/19 6/20 1.6 % 0.84 [ 0.21, 3.32 ]
Wiener 1995 11/30 15/31 3.1 % 0.62 [ 0.23, 1.71 ]
Subtotal (95% CI) 767 830 65.3 % 0.96 [ 0.78, 1.20 ]

Total (95% CI) 1301 1529 100.0 % 0.97 [ 0.81, 1.16 ]
0.1 0.2 0.5 1.0 2.0 5.0 10.0

Ferrer 1992 15/51 14/50 4.2 % 1.07 [ 0.45, 2.52 ]
Gaussorgues 1991 29/59 29/59 6.0 % 1.00 [ 0.49, 2.05 ]
Hammond 1992 34/162 31/160 10.5 % 1.10 [ 0.64, 1.90 ]
Laggner 1994 9/33 14/34 3.1 % 0.54 [ 0.20, 1.48 ]
Lingnau 1997 9/90 17/177 4.3 % 1.05 [ 0.45, 2.46 ]
Lingnau 1997b 13/90 17/177 4.8 % 1.62 [ 0.73, 3.62 ]
Stoutenbeek 1996 2/49 8/42 1.8 % 0.22 [ 0.06, 0.82 ]
Subtotal (95% CI) 534 699 34.7 % 0.98 [ 0.73, 1.32 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Bergmans 2001 30/87 59/139 10.4 % 0.72 [ 0.42, 1.24 ]
Brun-Buisson 1989 14/65 15/68 4.6 % 0.97 [ 0.43, 2.20 ]
Cerra 1992 13/25 10/23 2.5 % 1.40 [ 0.46, 4.29 ]
Gastinne 1992 88/220 82/225 21.3 % 1.16 [ 0.79, 1.70 ]
Georges 1994 3/31 5/33 1.4 % 0.61 [ 0.14, 2.66 ]
Korinek 1993 22/96 17/95 6.3 % 1.36 [ 0.67, 2.74 ]
Pneumatikos 2002 5/31 7/30 2.0 % 0.64 [ 0.18, 2.23 ]
Pugin 1991 10/38 11/41 3.2 % 0.97 [ 0.36, 2.63 ]
Quinio 1995 12/76 10/73 3.8 % 1.18 [ 0.48, 2.91 ]
Rodriguez-Rolda 1990 5/14 7/17 1.5 % 0.80 [ 0.19, 3.34 ]
Unertl 1987 5/19 6/20 1.6 % 0.84 [ 0.21, 3.32 ]
Wiener 1995 11/30 15/31 3.1 % 0.62 [ 0.23, 1.71 ]
Subtotal (95% CI) 767 830 65.3 % 0.96 [ 0.78, 1.20 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Analysis 2.2. Comparison 2 topical vs control, Outcome 2 mortality according to randomisation.
Lingnau 1997 9/90 17/177 9.7 % 1.05 [ 0.45, 2.46 ]
Lingnau 1997b 13/90 17/177 11.1 % 1.62 [ 0.73, 3.62 ]
Bergmans 2001 30/87 59/139 23.8 % 0.72 [ 0.42, 1.24 ]
Cerra 1992 13/25 10/23 5.7 % 1.40 [ 0.46, 4.29 ]
Georges 1994 3/31 5/33 3.3 % 0.61 [ 0.14, 2.66 ]
Korinek 1993 22/96 17/95 14.4 % 1.36 [ 0.67, 2.74 ]
Pugin 1991 10/38 11/41 7.2 % 0.97 [ 0.36, 2.63 ]
Quinio 1995 12/76 10/73 8.7 % 1.18 [ 0.48, 2.91 ]
Stoutenbeek 1996 2/49 8/42 4.1 % 0.22 [ 0.06, 0.82 ]
Unertl 1987 5/19 6/20 3.7 % 0.84 [ 0.21, 3.32 ]
Subtotal (95% CI) 636 855 100.0 % 0.93 [ 0.72, 1.22 ]

Brun-Buisson 1989 14/65 15/68 8.2 % 0.97 [ 0.43, 2.20 ]
Ferrer 1992 15/51 14/50 7.5 % 1.07 [ 0.45, 2.52 ]
Gastinne 1992 88/220 82/225 37.8 % 1.16 [ 0.79, 1.70 ]
Gaussorgues 1991 29/59 29/59 10.7 % 1.00 [ 0.49, 2.05 ]
Hammond 1992 34/162 31/160 18.7 % 1.10 [ 0.64, 1.90 ]
Laggner 1994 9/33 14/34 5.5 % 0.54 [ 0.20, 1.48 ]
Pneumatikos 2002 5/31 7/30 3.5 % 0.64 [ 0.18, 2.23 ]
Rodriguez-Rolda 1990 5/14 7/17 2.7 % 0.80 [ 0.19, 3.34 ]
Wiener 1995 11/30 15/31 5.4 % 0.62 [ 0.23, 1.71 ]
Subtotal (95% CI) 665 674 100.0 % 1.00 [ 0.79, 1.26 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Lingnau 1997 9/90 17/177 9.7 % 1.05 [ 0.45, 2.46 ]
Lingnau 1997b 13/90 17/177 11.1 % 1.62 [ 0.73, 3.62 ]
Bergmans 2001 30/87 59/139 23.8 % 0.72 [ 0.42, 1.24 ]
Cerra 1992 13/25 10/23 5.7 % 1.40 [ 0.46, 4.29 ]
Georges 1994 3/31 5/33 3.3 % 0.61 [ 0.14, 2.66 ]
Korinek 1993 22/96 17/95 14.4 % 1.36 [ 0.67, 2.74 ]
Pugin 1991 10/38 11/41 7.2 % 0.97 [ 0.36, 2.63 ]
Quinio 1995 12/76 10/73 8.7 % 1.18 [ 0.48, 2.91 ]
Stoutenbeek 1996 2/49 8/42 4.1 % 0.22 [ 0.06, 0.82 ]
Unertl 1987 5/19 6/20 3.7 % 0.84 [ 0.21, 3.32 ]
Subtotal (95% CI) 636 855 100.0 % 0.93 [ 0.72, 1.22 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Brun-Buisson 1989 14/65 15/68 8.2 % 0.97 [ 0.43, 2.20 ]
Ferrer 1992 15/51 14/50 7.5 % 1.07 [ 0.45, 2.52 ]
Gastinne 1992 88/220 82/225 37.8 % 1.16 [ 0.79, 1.70 ]
Gaussorgues 1991 29/59 29/59 10.7 % 1.00 [ 0.49, 2.05 ]
Hammond 1992 34/162 31/160 18.7 % 1.10 [ 0.64, 1.90 ]
Laggner 1994 9/33 14/34 5.5 % 0.54 [ 0.20, 1.48 ]
Pneumatikos 2002 5/31 7/30 3.5 % 0.64 [ 0.18, 2.23 ]
Rodriguez-Rolda 1990 5/14 7/17 2.7 % 0.80 [ 0.19, 3.34 ]
Wiener 1995 11/30 15/31 5.4 % 0.62 [ 0.23, 1.71 ]
Subtotal (95% CI) 665 674 100.0 % 1.00 [ 0.79, 1.26 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Analysis 2.3. Comparison 2 topical vs control, Outcome 3 mortality according to blinding of the studies.
1 double-blind
Bergmans 2001 30/87 57/139 12.5 % 0.76 [ 0.44, 1.32 ]
Cerra 1992 12/25 10/23 3.0 % 1.20 [ 0.39, 3.68 ]
Ferrer 1992 15/51 14/50 5.1 % 1.07 [ 0.45, 2.52 ]
Gastinne 1992 88/220 82/225 25.8 % 1.16 [ 0.79, 1.70 ]
Hammond 1992 34/162 31/160 12.7 % 1.10 [ 0.64, 1.90 ]
Korinek 1993 22/96 17/95 7.6 % 1.36 [ 0.67, 2.74 ]
Laggner 1994 9/33 14/34 3.8 % 0.54 [ 0.20, 1.48 ]
Lingnau 1997 9/90 17/177 5.2 % 1.05 [ 0.45, 2.46 ]
Lingnau 1997b 13/90 17/177 5.8 % 1.62 [ 0.73, 3.62 ]
Pneumatikos 2002 5/31 7/30 2.4 % 0.64 [ 0.18, 2.23 ]
Pugin 1991 10/38 11/41 3.8 % 0.97 [ 0.36, 2.63 ]
Quinio 1995 12/76 10/73 4.6 % 1.18 [ 0.48, 2.91 ]
Rodriguez-Rolda 1990 5/14 7/17 1.8 % 0.80 [ 0.19, 3.34 ]
Stoutenbeek 1996 2/49 8/42 2.2 % 0.22 [ 0.06, 0.82 ]
Wiener 1995 11/30 15/31 3.7 % 0.62 [ 0.23, 1.71 ]
Subtotal (95% CI) 1092 1314 100.0 % 1.00 [ 0.82, 1.21 ]

2 unblind
Georges 1994 3/31 5/33 8.3 % 0.61 [ 0.14, 2.66 ]
Brun-Buisson 1989 14/65 15/68 26.7 % 0.97 [ 0.43, 2.20 ]
Gaussorgues 1991 29/59 29/59 34.8 % 1.00 [ 0.49, 2.05 ]
Unertl 1987 5/19 6/20 9.5 % 0.84 [ 0.21, 3.32 ]
Subtotal (95% CI) 209 215 100.0 % 0.85 [ 0.56, 1.30 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
1 double-blind
Bergmans 2001 30/87 57/139 12.5 % 0.76 [ 0.44, 1.32 ]
Cerra 1992 12/25 10/23 3.0 % 1.20 [ 0.39, 3.68 ]
Ferrer 1992 15/51 14/50 5.1 % 1.07 [ 0.45, 2.52 ]
Gastinne 1992 88/220 82/225 25.8 % 1.16 [ 0.79, 1.70 ]
Hammond 1992 34/162 31/160 12.7 % 1.10 [ 0.64, 1.90 ]
Korinek 1993 22/96 17/95 7.6 % 1.36 [ 0.67, 2.74 ]
Laggner 1994 9/33 14/34 3.8 % 0.54 [ 0.20, 1.48 ]
Lingnau 1997 9/90 17/177 5.2 % 1.05 [ 0.45, 2.46 ]
Lingnau 1997b 13/90 17/177 5.8 % 1.62 [ 0.73, 3.62 ]
Pneumatikos 2002 5/31 7/30 2.4 % 0.64 [ 0.18, 2.23 ]
Pugin 1991 10/38 11/41 3.8 % 0.97 [ 0.36, 2.63 ]
Quinio 1995 12/76 10/73 4.6 % 1.18 [ 0.48, 2.91 ]
Rodriguez-Rolda 1990 5/14 7/17 1.8 % 0.80 [ 0.19, 3.34 ]
Stoutenbeek 1996 2/49 8/42 2.2 % 0.22 [ 0.06, 0.82 ]
Wiener 1995 11/30 15/31 3.7 % 0.62 [ 0.23, 1.71 ]
Subtotal (95% CI) 1092 1314 100.0 % 1.00 [ 0.82, 1.21 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
2 unblind
Georges 1994 3/31 5/33 8.3 % 0.61 [ 0.14, 2.66 ]
Brun-Buisson 1989 14/65 15/68 26.7 % 0.97 [ 0.43, 2.20 ]
Gaussorgues 1991 29/59 29/59 34.8 % 1.00 [ 0.49, 2.05 ]
Unertl 1987 5/19 6/20 9.5 % 0.84 [ 0.21, 3.32 ]
Subtotal (95% CI) 209 215 100.0 % 0.85 [ 0.56, 1.30 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Analysis 2.4. Comparison 2 topical vs control, Outcome 4 RTIs.
Outcome: 4 RTIs

Ferrer 1992 7/51 11/50 3.4 % 0.57 [ 0.21, 1.58 ]
Hammond 1992 25/162 30/160 10.4 % 0.79 [ 0.44, 1.41 ]
Laggner 1994 1/33 4/34 1.1 % 0.29 [ 0.05, 1.76 ]
Lingnau 1997 38/90 71/177 13.2 % 1.09 [ 0.65, 1.83 ]
Lingnau 1997b 34/90 71/177 13.0 % 0.91 [ 0.54, 1.52 ]
Stoutenbeek 1996 2/49 8/42 2.0 % 0.22 [ 0.06, 0.82 ]
Subtotal (95% CI) 475 640 43.1 % 0.81 [ 0.61, 1.08 ]
0.1 0.2 0.5 1.0 2.0 5.0 10.0

(Continued . . . )
(. . . Continued)
Bergmans 2001 9/87 38/139 8.1 % 0.36 [ 0.19, 0.69 ]
Brun-Buisson 1989 3/65 6/68 1.9 % 0.52 [ 0.13, 1.99 ]
Gastinne 1992 26/220 33/225 11.7 % 0.78 [ 0.45, 1.35 ]
Georges 1994 4/31 15/33 3.1 % 0.22 [ 0.07, 0.62 ]
Korinek 1993 20/96 37/95 9.1 % 0.42 [ 0.23, 0.78 ]
Pneumatikos 2002 5/31 16/30 3.2 % 0.20 [ 0.07, 0.56 ]
Pugin 1991 4/38 24/41 4.2 % 0.13 [ 0.05, 0.32 ]
Quinio 1995 19/76 38/73 8.1 % 0.32 [ 0.17, 0.62 ]
Rodriguez-Rolda 1990 1/14 11/17 1.7 % 0.10 [ 0.02, 0.40 ]
Unertl 1987 1/19 9/20 1.7 % 0.13 [ 0.03, 0.54 ]
Wiener 1995 8/30 8/31 2.7 % 1.04 [ 0.34, 3.24 ]
Subtotal (95% CI) 742 807 56.9 % 0.37 [ 0.29, 0.48 ]

Total (95% CI) 1217 1447 100.0 % 0.52 [ 0.43, 0.63 ]
0.1 0.2 0.5 1.0 2.0 5.0 10.0
Outcome: 4 RTIs

Ferrer 1992 7/51 11/50 3.4 % 0.57 [ 0.21, 1.58 ]
Hammond 1992 25/162 30/160 10.4 % 0.79 [ 0.44, 1.41 ]
Laggner 1994 1/33 4/34 1.1 % 0.29 [ 0.05, 1.76 ]
Lingnau 1997 38/90 71/177 13.2 % 1.09 [ 0.65, 1.83 ]
Lingnau 1997b 34/90 71/177 13.0 % 0.91 [ 0.54, 1.52 ]
Stoutenbeek 1996 2/49 8/42 2.0 % 0.22 [ 0.06, 0.82 ]
Subtotal (95% CI) 475 640 43.1 % 0.81 [ 0.61, 1.08 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Outcome: 4 RTIs
Bergmans 2001 9/87 38/139 8.1 % 0.36 [ 0.19, 0.69 ]
Brun-Buisson 1989 3/65 6/68 1.9 % 0.52 [ 0.13, 1.99 ]
Gastinne 1992 26/220 33/225 11.7 % 0.78 [ 0.45, 1.35 ]
Georges 1994 4/31 15/33 3.1 % 0.22 [ 0.07, 0.62 ]
Korinek 1993 20/96 37/95 9.1 % 0.42 [ 0.23, 0.78 ]
Pneumatikos 2002 5/31 16/30 3.2 % 0.20 [ 0.07, 0.56 ]
Pugin 1991 4/38 24/41 4.2 % 0.13 [ 0.05, 0.32 ]
Quinio 1995 19/76 38/73 8.1 % 0.32 [ 0.17, 0.62 ]
Rodriguez-Rolda 1990 1/14 11/17 1.7 % 0.10 [ 0.02, 0.40 ]
Unertl 1987 1/19 9/20 1.7 % 0.13 [ 0.03, 0.54 ]
Wiener 1995 8/30 8/31 2.7 % 1.04 [ 0.34, 3.24 ]
Subtotal (95% CI) 742 807 56.9 % 0.37 [ 0.29, 0.48 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Analysis 2.5. Comparison 2 topical vs control, Outcome 5 RTIs according to randomisation.
Lingnau 1997 38/90 71/177 20.6 % 1.09 [ 0.65, 1.83 ]
Lingnau 1997b 34/90 71/177 20.4 % 0.91 [ 0.54, 1.52 ]
Bergmans 2001 9/87 38/139 12.6 % 0.36 [ 0.19, 0.69 ]
Georges 1994 4/31 15/33 4.8 % 0.22 [ 0.07, 0.62 ]
Korinek 1993 20/96 37/95 14.3 % 0.42 [ 0.23, 0.78 ]
Pugin 1991 4/38 24/41 6.5 % 0.13 [ 0.05, 0.32 ]
Quinio 1995 19/76 38/73 12.6 % 0.32 [ 0.17, 0.62 ]
Stoutenbeek 1996 2/49 8/42 3.2 % 0.22 [ 0.06, 0.82 ]
Unertl 1987 1/19 9/20 2.7 % 0.13 [ 0.03, 0.54 ]
Subtotal (95% CI) 611 832 100.0 % 0.49 [ 0.39, 0.62 ]

Ferrer 1992 7/51 11/50 9.4 % 0.57 [ 0.21, 1.58 ]
Brun-Buisson 1989 3/65 6/68 5.3 % 0.52 [ 0.13, 1.99 ]
Gastinne 1992 26/220 33/225 32.3 % 0.78 [ 0.45, 1.35 ]
Hammond 1992 25/162 30/160 28.8 % 0.79 [ 0.44, 1.41 ]
Laggner 1994 1/33 4/34 3.0 % 0.29 [ 0.05, 1.76 ]
Pneumatikos 2002 5/31 16/30 8.8 % 0.20 [ 0.07, 0.56 ]
Rodriguez-Rolda 1990 1/14 11/17 4.7 % 0.10 [ 0.02, 0.40 ]
Wiener 1995 8/30 8/31 7.6 % 1.04 [ 0.34, 3.24 ]
Subtotal (95% CI) 606 615 100.0 % 0.59 [ 0.43, 0.81 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Lingnau 1997 38/90 71/177 20.6 % 1.09 [ 0.65, 1.83 ]
Lingnau 1997b 34/90 71/177 20.4 % 0.91 [ 0.54, 1.52 ]
Bergmans 2001 9/87 38/139 12.6 % 0.36 [ 0.19, 0.69 ]
Georges 1994 4/31 15/33 4.8 % 0.22 [ 0.07, 0.62 ]
Korinek 1993 20/96 37/95 14.3 % 0.42 [ 0.23, 0.78 ]
Pugin 1991 4/38 24/41 6.5 % 0.13 [ 0.05, 0.32 ]
Quinio 1995 19/76 38/73 12.6 % 0.32 [ 0.17, 0.62 ]
Stoutenbeek 1996 2/49 8/42 3.2 % 0.22 [ 0.06, 0.82 ]
Unertl 1987 1/19 9/20 2.7 % 0.13 [ 0.03, 0.54 ]
Subtotal (95% CI) 611 832 100.0 % 0.49 [ 0.39, 0.62 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Ferrer 1992 7/51 11/50 9.4 % 0.57 [ 0.21, 1.58 ]
Brun-Buisson 1989 3/65 6/68 5.3 % 0.52 [ 0.13, 1.99 ]
Gastinne 1992 26/220 33/225 32.3 % 0.78 [ 0.45, 1.35 ]
Hammond 1992 25/162 30/160 28.8 % 0.79 [ 0.44, 1.41 ]
Laggner 1994 1/33 4/34 3.0 % 0.29 [ 0.05, 1.76 ]
Pneumatikos 2002 5/31 16/30 8.8 % 0.20 [ 0.07, 0.56 ]
Rodriguez-Rolda 1990 1/14 11/17 4.7 % 0.10 [ 0.02, 0.40 ]
Wiener 1995 8/30 8/31 7.6 % 1.04 [ 0.34, 3.24 ]
Subtotal (95% CI) 606 615 100.0 % 0.59 [ 0.43, 0.81 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
Analysis 2.6. Comparison 2 topical vs control, Outcome 6 RTIs according to blinding of the studies.
1 double-blind
Ferrer 1992 7/51 11/50 3.7 % 0.57 [ 0.21, 1.58 ]
Bergmans 2001 9/87 38/139 8.8 % 0.36 [ 0.19, 0.69 ]
Gastinne 1992 26/220 33/225 12.7 % 0.78 [ 0.45, 1.35 ]
Hammond 1992 25/162 30/160 11.3 % 0.79 [ 0.44, 1.41 ]
Korinek 1993 20/96 37/95 10.0 % 0.42 [ 0.23, 0.78 ]
Laggner 1994 1/33 4/34 1.2 % 0.29 [ 0.05, 1.76 ]
Lingnau 1997 38/90 71/177 14.3 % 1.09 [ 0.65, 1.83 ]
Lingnau 1997b 34/90 71/177 14.2 % 0.91 [ 0.54, 1.52 ]
Pneumatikos 2002 5/31 16/30 3.5 % 0.20 [ 0.07, 0.56 ]
Pugin 1991 4/38 24/41 4.5 % 0.13 [ 0.05, 0.32 ]
Quinio 1995 19/76 38/73 8.8 % 0.32 [ 0.17, 0.62 ]
Rodriguez-Rolda 1990 1/14 11/17 1.9 % 0.10 [ 0.02, 0.40 ]
Stoutenbeek 1996 2/49 8/42 2.2 % 0.22 [ 0.06, 0.82 ]
Wiener 1995 8/30 8/31 3.0 % 1.04 [ 0.34, 3.24 ]
Subtotal (95% CI) 1067 1291 100.0 % 0.55 [ 0.45, 0.67 ]

2 unblind
Georges 1994 4/31 15/33 37.6 % 0.22 [ 0.07, 0.62 ]
Brun-Buisson 1989 3/65 6/68 23.5 % 0.52 [ 0.13, 1.99 ]
Unertl 1987 1/19 9/20 21.2 % 0.13 [ 0.03, 0.54 ]
Subtotal (95% CI) 150 156 100.0 % 0.30 [ 0.15, 0.57 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
1 double-blind
Ferrer 1992 7/51 11/50 3.7 % 0.57 [ 0.21, 1.58 ]
Bergmans 2001 9/87 38/139 8.8 % 0.36 [ 0.19, 0.69 ]
Gastinne 1992 26/220 33/225 12.7 % 0.78 [ 0.45, 1.35 ]
Hammond 1992 25/162 30/160 11.3 % 0.79 [ 0.44, 1.41 ]
Korinek 1993 20/96 37/95 10.0 % 0.42 [ 0.23, 0.78 ]
Laggner 1994 1/33 4/34 1.2 % 0.29 [ 0.05, 1.76 ]
Lingnau 1997 38/90 71/177 14.3 % 1.09 [ 0.65, 1.83 ]
Lingnau 1997b 34/90 71/177 14.2 % 0.91 [ 0.54, 1.52 ]
Pneumatikos 2002 5/31 16/30 3.5 % 0.20 [ 0.07, 0.56 ]
Pugin 1991 4/38 24/41 4.5 % 0.13 [ 0.05, 0.32 ]
Quinio 1995 19/76 38/73 8.8 % 0.32 [ 0.17, 0.62 ]
Rodriguez-Rolda 1990 1/14 11/17 1.9 % 0.10 [ 0.02, 0.40 ]
Stoutenbeek 1996 2/49 8/42 2.2 % 0.22 [ 0.06, 0.82 ]
Wiener 1995 8/30 8/31 3.0 % 1.04 [ 0.34, 3.24 ]
Subtotal (95% CI) 1067 1291 100.0 % 0.55 [ 0.45, 0.67 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
2 unblind
Georges 1994 4/31 15/33 37.6 % 0.22 [ 0.07, 0.62 ]
Brun-Buisson 1989 3/65 6/68 23.5 % 0.52 [ 0.13, 1.99 ]
Unertl 1987 1/19 9/20 21.2 % 0.13 [ 0.03, 0.54 ]
Subtotal (95% CI) 150 156 100.0 % 0.30 [ 0.15, 0.57 ]

0.1 0.2 0.5 1.0 2.0 5.0 10.0
WHAT’S NEW
Last assessed as up-to-date: 25 November 2003.
7 July 2008 Amended Converted to new review format.
HISTORY
Review first published: Issue 3, 1997
25 November 2003 Amended Old title ’Antibitoics for preventing respiratory tract infections in adults
receiving intensive care’ changed in issue 1, 2004
6 December 1999 New search has been performed Searches conducted
9 December 1995 New search has been performed Searches conducted.
CONTRIBUTIONS OF AUTHORS
Alessandro Liberati prepared the protocol and review, oversaw the data collection and critical appraisal of studies, updated the review
and prepared the final version of the manuscript.
Roberto D’Amico prepared the protocol and review, oversaw the data collection and critical appraisal of studies, carried out the statistical
analysis, updated the review and prepared the final version of the manuscript.
Luca Brazzi collaborated to the preparation of the protocol, the identification of trials and their critical appraisal.
Valter Torri collaborated to the preparation of the protocol and the statistical analysis.
Silvia Pifferi collaborated to the identification of trials and their critical appraisal.
DECLARATIONS OF INTEREST
None
SOURCES OF SUPPORT
Internal sources
• Italian Cochrane Centre, Italy.
External sources
• No sources of support supplied
INDEX TERMS
Medical Subject Headings (MeSH)
Anti-Bacterial Agents [therapeutic use]; ∗ Antibiotic Prophylaxis; Cross Infection [mortality; ∗ prevention & control]; Hospital Mortality;
∗ Intensive Care; Randomized Controlled Trials as Topic; Respiratory Tract Infections [mortality; ∗ prevention & control]
MeSH check words

Adult; Humans

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Antibiotic prophylaxis to reduce respiratory tract infections

and mortality in adults receiving intensive care (Review)

Liberati A, D’Amico R, Pifferi S, Torri V, Brazzi L

Antibiotic prophylaxis to reduce respiratory tract infections

PLAIN LANGUAGE SUMMARY

Criteria for considering studies for this review Electronic searches

Types of studies We searched the Cochrane Central Register of Controlled Trials

Methods Randomised study blinded for radiologic diagnosis

Outcomes Respiratory infections (acquired pneumonia):

Notes Data about 37 excluded patients are not available

Item Authors’ judgement Description

Allocation concealment? Unclear D - Not used

Interventions Group A, CTR 1:

Outcomes Respiratory infections (acquired pneumonia and tracheobronchitis):

Item Authors’ judgement Description

Allocation concealment? Unclear D - Not used

Methods Randomised, double blind, placebo-controlled study

Interventions Group A, Treatment:

Item Authors’ judgement Description

Allocation concealment? Unclear D - Not used

Methods Randomised study

Interventions Group A, CTR:

Item Authors’ judgement Description

Allocation concealment? Unclear D - Not used

Methods Randomised, placebo-controlled, double-blind study

Interventions Group A, CTR:

Outcomes Respiratory infections (acquired pneumonia and tracheobronchitis).

Item Authors’ judgement Description

Allocation concealment? Unclear D - Not used

Methods Randomised trial

Interventions Group A, Treatment:

Notes Setting: acute and intermediate areas of a medical ICU

Item Authors’ judgement Description

Allocation concealment? Unclear D - Not used

Methods Randomised, placebo-controlled, double-blind study

Interventions Group A, Treatment:

Outcomes Respiratory infections: not evaluable

Item Authors’ judgement Description

Allocation concealment? Unclear D - Not used

Methods Randomised study blinded for respiratory diagnosis. Intention to treat

Interventions Group A, CTR:

Outcomes Respiratory infections (only acquired infections).

Item Authors’ judgement Description

Allocation concealment? Unclear D - Not used

Methods Randomised study. Randomisation method:computer-generated random-number codes kept in sealed

Interventions SDD group:

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate

Methods Randomised, placebo-controlled, double-blind study

Interventions Group A, Treatment:

Outcomes Respiratory infections (pneumonia acquired after 4 days of mechanical ventilation)

Item Authors’ judgement Description

Allocation concealment? Unclear D - Not used

Methods Randomised study

Interventions Group A, Treatment:

Outcomes Respiratory infections (acquired pneumonia)

Item Authors’ judgement Description

Allocation concealment? Unclear D - Not used

Interventions Group A, CTR:

Outcomes Respiratory infections (pneumonia diagnosed within 48 hrs and acquired):