Antibiotics for preventing respiratory tract infections in adults receiving intensive care

Authors

  • A Liberati,

    Corresponding author
    1. Laboratory of Clinical Epidemiology, "Mario Negri Institute", Italian Cochrane Centre, Milano, ITALY
    • A Liberati, Italian Cochrane Centre, Laboratory of Clinical Epidemiology, "Mario Negri Institute", Via Eritrea 62, Milano, 20157, ITALY. Cochrane@irfmn.mnegri.it.

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  • R D'Amico,

  • S Pifferi,

  • C Leonetti,

  • V Torri,

  • L Brazzi,

  • A Tinazzi


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 infections, 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 Medline, the Cochrane Acute Respiratory Infections Group trials register, proceedings of scientific meetings and reference lists of articles from January 1984 to December 1999. 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

Investigators were contacted for additional information. At least two reviewers independently extracted data and assessed trial quality.

Main results

Overall 33 trials involving 5727 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 16 trials (involving 3361 patients) that tested a combination of topical and systemic antibiotic, the average rates of respiratory tract infections and deaths in the control group were 36% and 30% 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 0.80, 95% confidence interval 0.69 to 0.93) in the treated group. On average 5 patients needed to be treated to prevent one infection and 23 patients to prevent one death. In 17 trials (involving 2366 patients) that tested topical antimicrobials the rates of respiratory tract infections and deaths in the control groups were 28% and 26% respectively. There was a significant reduction of respiratory tract infections (odds ratio 0.56, 95% confidence interval 0.46 to 0.68) but not in total mortality (odds ratio 1.01, 95% confidence interval 0.84 to 1.22) in the treated group.

Reviewer's conclusions

A combination of topical and systemic prophylactic antibiotics can reduce respiratory tract infections and overall mortality in adult patients receiving intensive care. The design of the trials included in this systematic review does not allow to assess whether or not the treatment leads to antimicrobial resistance. Trials with different design are warranted to reliably address this question.

Plain language summary

Synopsis

Antibiotics can help reduce 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 infections and therefore death from these infections. The use of topical antibiotics alone will reduce the person's infection but not influence their survival.

Background

Nosocomial infections, especially pneumonia, are an important cause of morbidity and mortality in intensive care units (ICU). The incidence of pneumonia has been reported to vary from 7% to more than 40% in ICU patients. The crude mortality rate for patients with ventilator-associated pneumonia (VAP) may exceed 50%. Although not all deaths in patients with pneumonia are directly attributable to infection, pneumonia has been shown to contribute to ICU mortality independently of other factors that are also strongly associated with deaths of these patients (Fagon et al 1996). In a case-control study an increase in mortality of 27% attributable to pneumonia was evidenced in ventilated patients (Fagon et al 1993). Considerable efforts have been made to evaluate methods for reducing respiratory infection. One strategy involves the use of selective decontamination of the digestive tract (SDD). Different SDD protocols have been used in different trials and investigators often disagree on what the most appropriate definition of SDD is. Traditionally SDD indicates a method designed to prevent infection by eradicating and preventing carriage of aerobic potentially pathogenic micro-organisms from the oropharynx, stomach and gut. It consists of antimicrobials applied topically to the oropharynx and through a naso-gastric tube. In some trials systemic antibiotic therapy has been added in the first days after patients' admission to prevent 'early' infections. An SDD protocol based on oral non-absorbable antibiotics was first used in 1984 by Stoutenbeek in a group of multiple trauma patients. The incidence of nosocomial infection was reduced from 81% to 16% in a non-randomised comparison with a historical control group. Further studies tested the efficacy of SDD in ICU patients, with infection-related morbidity as the main point. The results showed that SDD reduced infection but it was not clear whether there was a reduction in mortality. Between 1991 and 1995 five different meta-analyses (Vanderbrouk-Grauls 1991, SDD Group 1993, Heyland 1994, Kollef 1994, Hurley 1995) on the effect of SDD on respiratory tract infections (RTIs) and mortality were published. Their results are summarised below:

Vanderbrouk-Grauls (number of studies = 6, number of patients = 491)
mortality: Odds Ratio (OR) 0.70, 95% Confidence Interval (CI) 0.45-1.09
RTIs: OR 0.12, 95%CI 0.08-0.19

SDD Group (number of studies = 22, number of patients = 4142)
mortality: OR 0.90, 95%CI 0.79-1.04
RTIs: OR 0.37, 95%CI 0.31-0.43

Heyland (number of studies = 24, number of patients = 3312)
mortality: Relative Risk (RR) 0.87, 95%CI 0.79-0.97
RTIs: RR 0.46, 95%CI 0.39-0.56

Kollef (number of studies = 16, number of patients = 2270)
mortality: Risk Difference (RD) 0.019, 95%CI -0.016 to 0.054
pneumonia: RD 0.145, 95%CI 0.116 to 0.174
tracheobronchitis: RD 0.052, 95%CI 0.017 to 0.087

Hurley (number of studies = 26, number of patients = 3768)
mortality: OR 0.86, 95%CI 0.74-0.99
RTIs: OR 0.35, 95%CI 0.30-0.42

All confirmed a statistically significant reduction in RTIs, though the magnitude of the treatment effect varied from one review to another. The estimated impact on overall mortality was less evident but the interpretation of these equivocal results could be better understood by the recently acquired awareness that - given the baseline risk of death in these populations - between 2 and 3,000 patients are needed to reliably detect a realistically achievable relative reduction in mortality lying in the 10%-20% range (SDD Group, 1993).
In order to shed further light on the issue we report here on an updated and refined meta-analysis made possible by the enthusiastic collaboration of the majority of trialists in the field. The main difference between this and previously published meta-analyses listed above is that here we looked at the effect of antibiotic prophylaxis separating trials where the protocol tested a systemic drug added to topical antimicrobials from those where topical antimicrobials only were tested. The results of this updated meta-analysis have already been published elsewhere (D'Amico, 1998).

Objectives

To determine whether antibiotic prophylaxis reduces RTIs and overall mortality in adult patients treated in ICUs.
Specifically, the main question left unanswered by existing randomised controlled trials (RCTs) and previous meta-analyses was whether different forms of antibiotic prophylaxis (i.e. the one testing topical antimicrobials or the one using a combination of topical and systemic drugs) are effective in reducing overall mortality.

Criteria for considering studies for this review

Types of studies

All RCTs, published and unpublished, without language restriction, and testing the effect of antibiotic prophylaxis for the prevention of RTIs and deaths in adult ICU patients were considered. Only randomised trials (RCTs) were accepted because otherwise control of selection bias could not be guaranteed; studies found - upon closer scrutiny - not to be randomised were not included.

Types of participants

Unselected adult general patients admitted to an ICU. Studies based on specific pre-selected types of patients (i.e. patients undergoing elective oesophageal resection, cardiac or gastric surgery, liver transplant or suffering from acute liver failure) were not included. Studies where the majority of patients (>50%) did not undergo mechanical ventilation for more than 48 hours were also excluded. The characteristics of excluded studies are reported in the table.

Types of intervention

Available RCTs have been grouped into two categories defined according to the type of antibiotic prophylaxis: a) studies where a combination of systemic and topical antibiotics was tested against no prophylactic treatment (thereafter referred as 'topical plus systemic vs no prophylaxis'); b) studies where the experimental treatment tested was a topical preparation (thereafter referred as 'topical vs control'). In this latter category two subgroups of RCTs have been lumped, i.e. those where topical antibiotics were tested against an untreated control group and those where the combination of topical plus systemic drugs was compared with a protocol based on a systemic antimicrobial only. Any topical or systemic antimicrobial combination (that is: type of drugs) was accepted, because there were not data to assume a difference in effect among the considered prophylactic treatments. This obviously does not mean that all topical regimens and all systemic regimens are truly equivalent but simply reflects our pragmatic working assumption.

Types of outcome measures

Two main outcomes were considered: RTIs and overall mortality.
No restriction was made on type of RTIs considered and on RTIs diagnostic criteria chosen by the trialists. Both tracheobronchitis and pneumonia were acceptable. Both primary (diagnosed within 48 hrs from admission) and acquired (diagnosed after 48 hrs from admission) infections were considered, even though we used data on acquired infections when both pieces of information were available. Mortality was evaluated at hospital discharge if this information was provided; otherwise mortality in ICU was considered.

Search strategy for identification of studies

See: Unavailable search strategy

The search for randomised control trials covered the time span from January 1984 to December 1999. Studies were identified by literature search MEDLINE (medical subject heading (MeSH) keywords: Intensive care units; Critical care; Antibiotic combined therapeutic use; Antibiotics combined administration and dosage; Respiratory tract infections prevention and control. Keyword: SDD). Other studies were evaluated because they were listed in previous meta-analyses. We also searched the Cochrane Acute Respiratory Infections Group trials register. The organiser of the first European Consensus Conference on Intensive Care Medicine (held in Paris on December 1991) also provided a list of all investigators who had ever published on the topic. An additional search focused on Proceedings of Scientific Meetings held on the subject and personal contacts were established with other known investigators in the field. No formal inquiry was made through pharmaceutical companies.

Methods of the review

It has been documented in a qualitative review of published studies (Brazzi et al. 1992) that in many published trials some patients had been excluded from the final analysis. Therefore we tried to contact all investigators (of both published and unpublished trials) to analyse the entire population originally enrolled into the trials (i.e. 'Intention to treat analysis'). In 25 out of 33 RCTs all randomised patients could be included in the analysis according to their original allocated treatment arm following the 'intention to treat' principle. This could not be performed in the following RCTs: Finch, Rocha, Verwaest for RTIs only and Abele-Horn, Laggner, Lenhart, Wiener and Georges for both RTIs and mortality. Data on key variables relevant for this review were available from published reports of RCTs. For 30 RCTs, however, published figures were integrated with the following information obtained, in a standardised format, directly through personal contacts with study investigators:
-Number of patients and their treatment allocation arm
-Method of randomisation and use of blinding techniques
-Type of comparison (type and dosage of antibiotic regimen)
-Number of patients with at least one RTI by treatment arm
-Number of deaths by treatment arm
-Number of excluded patients, number of RTIs and deaths among them

These contacts also gave us the opportunity to acquire further information on trial design, and overall policies in the ICUs where the trials had been conducted exploring issues such as: eligibility criteria, exclusion criteria, percentage of ventilated patients, patients' median length of stay in ICU, percentage of medical, surgical and trauma admissions, percentage of patients treated with systemic antibiotic therapy (not established in the protocol of the study) in the first three days of the study, frequency of use of stress ulcer prophylaxis and information on the methods used to diagnose RTIs.
Crude proportions of RTIs and mortality were our main treatment end-points. In addition to odds ratios of each outcome in each trial, computed with the fixed effects model, we computed the number of ICU patients who need to be treated in order to prevent one infection and one death. The calculation was based on the median rates of RTIs and deaths in untreated controls and the common odds ratio for all trials.
Two pre-specified subgroup analyses based on quality criteria were carried out within the two main groups of RCTs above specified:
-Quality of randomisation procedures ('blind' vs 'open')
-Blinding of patients and doctors to allocated treatment ('double-blind' vs 'unblind').

Description of studies

Forty-two potentially eligible RCTs were identified: 9 were excluded (see table) [Hunefeld 1989; Lipman 1994 1994; Bion 1994; Flaherty 1990; Luiten 1995; Martinez PAE 1994; Martinez-Pellus 2 1993; Rolando 1996; Schardey 1994; Tetteroo 1990], leaving 33 studies for this meta-analysis: 31 were published (27 in full form and four in abstract form) and 2 unpublished. Sixteen RCTs (totalling 3361 patients) compared topical and systemic antibiotic treatment versus no treatment/placebo, 11 RCTs (totalling 1310 patients) compared topical treatment to no treatment or placebo, and six trials (totalling 1056 patients) compared topical and systemic antibiotic treatment versus systemic antibiotic only.
We included studies by Laggner and Gaussorgues among the 'topical SDD plus systemic antibiotic versus systemic antibiotic' group even if their design did not foresee explicitly the use of systemic antibiotics because all patients in both arms were treated with systemic antibiotics on admission. Conversely, we included Jacobs 1992a [Jacobs 1992] study among the 'topical SDD plus systemic antibiotics versus control' group even if more than 90% of patients received a systemic antibiotic on admission because the treated arm was scheduled to receive also Cefotaxime intravenously. The 4 studies with a three arms comparison have been analysed as follows. In one study [Aerdts 1991] the two control groups were pooled together and compared to the treatment group. In 2 other studies [Lingnau ; Verwaest 1997] we split the study into two comparisons in which two different treatment arms were compared to the same control arm. In 1 study [Palomar, 1992] one of the two control arms was excluded because it received only sucralfate.
Overall, the total number of patients randomised to either antibiotic prophylaxis or placebo/ no treatment available for this review is 5727. Final meta-analysis was based upon 33 trials with 35 comparisons.
A few studies [Cerra, 1992; Gaussorgues, 1991; Lenhart, 1994] could not contribute to the RTIs analysis as they reported the number of episodes of RTIs and not the number of infected patients leaving 30 trials (totalling 4898 patients) for the final analysis. Mortality was evaluated in ICU in 23 trials (3371 patients); hospital mortality was available only for seven RCTs (1650 patients), the exact time of assessment of mortality was not determined in two trials [Jacobs 1992; Lenhart, 1994]. Most RCTs included general ICU patients. A few trials included only trauma [Boland, 1991; Georges, 1994; Lingnau 1997; Quinio. 1996; Stoutenbeek, 1996 and Stoutenbeek unpublished] or surgical patients [Cerra, 1992]. All patients were mechanically ventilated in 25 studies, the percentage of ventilated patients was lower in five trials [Blair 1991; Brun-Buisson 1989; Cockerill. 1992; Ulrich. 1989; Winter. 1992] and unknown in three [Cerra. 1992; Finch. 1991; Lenhart. 1994]. Only in Brun-Buisson's study the percentage of ventilated patients was very low (59%) probably because the setting of the study includes both 'acute' and 'intermediate' areas of a medical ICU.
The percentage of immunocompromised patients was usually lower than 10%; it was higher only in five trials [Brun-Buisson 1989; Finch 1991; Gastinne 1992; Jacobs 1992b; Laggner 1994]. Sucralfate was routinely used in all patients for stress ulcer prophylaxis in eight trials [Abele-Horn 1997; Ferrer 1994; Gaussorgues 1991, Jacobs 1992a 1992; Laggner 1994; Lenhart 1994; Quinio 1996 and Verwaest 1997]. In many RCTs only respiratory tract infections (RTIs) acquired in ICU (i.e. diagnosed after 48 hrs from admission) have been considered. Data on primary and acquired infections are considered together only in three trials [Boland 1991; Stoutenbeek 1 and 2]. Most studies (22 RCTs) evaluated only the occurrence of pneumonia while seven RCTs evaluated tracheobronchitis too; information was lacking in one RCT. Diagnostic criteria differed across trials. Few authors provide quantitative details on the cut-off point used as positive bacteriological confirmation. Six RCTs required a bacteriological confirmation obtained through a protected catheter brush or a BAL (Broncho-Alveolar Lavage) to make diagnosis of pneumonia; 14 trials established that a positive tracheal aspirate was adequate; 9 RCTs established that no bacteriological confirmation was required to make diagnosis of RTIs and in 1 trial the information was not available.

Methodological quality

Study quality was assessed looking at two criteria: a) methods of randomisation ('blind' vs 'open'); b) use of blinding techniques ('double blind' vs 'unblind' studies). The randomisation procedure was defined 'blind' when it was done by telephone through a pharmacy or a central office (7 trials) or using sealed envelopes (15 RCTs). It was defined 'open' when it was done using a computer generated list (6 RCTs) or when patients were allocated by odd-even number (4 RCTs). One RCT [Lenhart, 1994] - where the information on randomisation procedure was not available - was included by default into the 'open' category. Randomisation was therefore classified as 'blind' in 22 RCTs (3738 patients) and 'open' in 11 (1989 patients). Sixteen RCTs adopted a 'double blind' (2955 patients) and 17 an 'unblind' design (2772 patients).

Results

Respiratory tract infection

Results from 30 RCTs including 4898 patients were available for the analysis of the effects of different types of antibiotic prophylaxis on RTIs. The frequency of RTIs was 16% among treated patients and 36% among controls in RCTs using a combination of topical plus systemic antibiotic and 18% and 28%, respectively, in RCTs testing the effectiveness of topical prophylaxis. Overall, the odds ratio was lower than unity in all but 2 trials [Lingnau 1997; Wiener, 1995] and reached conventional statistical significance (p<0.05) in 21/32 comparisons.
Results indicate a strong protective effect in RCTs where the combination of topical and systemic treatment (OR = 0.35, 95%CI = 0.29-0.41) was tested. A significant protection emerged when topical prophylaxis was considered (OR = 56 95% CI = 0.46-0.68). The effect was stronger in RCTs where topical antimicrobials were tested against no prophylaxis (OR = 0.39, 95% CI = 0.30-0.52). Less extreme results were observed in trials testing the combination of topical and systemic antibiotic against systemic prophylaxis (OR = 0.81, 95% CI = 0.61-1.08).
These results indicate that 5 (95% CI = 4-5) or 9 (95% CI = 7-13) patients need to be treated to prevent one infection depending on whether a combination of topical and systemic treatment or topical antimicrobials were tested (assuming, as baseline risk, the median values of 44% and 32%, respectively, among control patients). Pre-defined subgroup analyses failed to show any effect on the estimates of treatment effect by quality of randomisation and blinding status of the RCTs..

Mortality

Overall, 33 RCTs including 5727 patients were available for the mortality analysis. The mortality was 24% among treated patients and 30% among controls on RCTs using a combination of topical plus systemic antibiotic; while it was 26% and 26%, respectively, on RCTs testing the effectiveness of topical SDD. The odds ratio was lower than unity in 23/35 comparisons but reached conventional statistical significance in only 2 RCTs [Lenhart, 1994; Stoutenbeek, 1996]; no trial showed a significant harmful effect of antibiotic prophylaxis.
Results indicate a statistically significant reduction in mortality attributable to the use of a combination of topical and systemic treatment (OR = 0.80, 95%CI = 0.69-0.93). This suggests that 23 patients (95%CI = 14-68) (assuming a baseline risk of 29%, median among control patients) need to be treated to prevent one death. On the other hand, no treatment effect emerged when RCTs testing topical antimicrobials were analysed (OR = 1.01; 95% CI = 0.84-1.22). In subgroup analyses by quality and randomisation and blinding status the treatment effect was particularly significant in RCTs testing the combined treatment and carried out using a 'double-blind' design (OR = 0.63; 95% CI = 0.48-0.83) compared to 'unblinded' studies (OR = 0.90; 95% CI = 0.74-1.08).

Discussion

Ever since its introduction as an infection prevention method in critically ill patients antibiotic prophylaxis based on SDD has remained controversial (Stoutenbeek, 1984). Lack of standard protocol and insufficient numbers of patients have made it difficult to derive meaningful conclusions from individual clinical trials. After an initial enthusiasm following results from early uncontrolled studies and initial randomised controlled trials (RCTs), antibiotic prophylaxis does not seem to be widely used as routine treatment in ICUs. The concern about the risk of long term emergence of antimicrobial resistance and increased costs dominates in the most important documents on prevention of infections as the 'Guidelines for Prevention of Nosocomial Pneumonia' recently published by the Centre of Disease Control and Prevention (Tablan, 1994) and the Consensus Statement of the American Thoracic Society on 'Hospital-Acquired Pneumonia in Adults' (Am Thoracic Society 1995). A conservative attitude in introducing a new treatment into practice is understandable as long as doubts on its efficacy exist. In fact studies on prevention of ventilator-associated pneumonia in ICU patients are very complex because patients are heterogeneous, diagnosis of pneumonia is controversial and outcome depends on so many factors. Despite the ability of antibiotic prophylaxis to reduce respiratory tract infections (RTIs) emerging with remarkable consistency across individual trials, the effect on mortality was statistically significant in only two trials. An historical examination of review articles and editorials in this area indicates that it was never fully realised that this could have been due to the small sample sizes of individual studies.
The meta-analysis reported here combines data across studies in order to estimate treatment effects with more precision than is possible in a single study. The main limitation of this metanalysis, as with any overview, is that the patient population, the antibiotic regimen and the outcome definitions are not the same across studies. Nonetheless, we believe that it provides the best global picture of the effectiveness of the intervention. Compared to the first five published meta-analyses (Vanderbrouk-Grauls 1991, SDD Group 1993, Heyland 1994, Kollef 1994, Hurley 1995) we decided to analyse separately trials testing a combination of systemic and topical antibiotics and those testing topical antimicrobials. Though there is no consensus on the best way to classify antibiotic prophylaxis regimens (Am Thoracic Society, 1995), it seemed eventually more appropriate to consider the two groups of trials as two distinct approaches to antibiotic prophylaxis.
The results of this meta-analysis confirm that both types of prophylaxis have a strong protective effect on RTIs - with the effect being more marked when patients are treated with a protocol using topical plus systemic antibiotics. This effect looks consistent in all subgroup analyses regardless of study design (blind/open randomisation, double-blind/unblind studies). Overall, these results appear convincing even though it is acknowledged that no diagnostic test or procedure is ideal to diagnose RTIs in ICU patients.
More importantly, this meta-analysis indicates that when a protocol of antibiotic prophylaxis that includes a combination of topical and systemic antibiotics is used there is a statistically significant reduction of overall mortality. The treatment effect suggested by this systematic review looks important from a clinical and public health point of view (in terms of the therapeutic implications for the care of ventilated patients in ICUs) and is also relevant from the scientific standpoint as it highlights the future directions that research in the field should take.
Given the enthusiastic collaboration provided by most investigators and the efforts to include also unpublished studies, it is unlikely that we have missed any important trial conducted so far. Moreover, as the vast majority of trials did not show statistically significant reduction in mortality on their own, there is no good reason to believe that publication bias represents a major problem in this literature.

Reviewer's conclusions

Implications for practice

This systematic review indicates that a protocol testing a combination of topical and systemic antibiotics reduces the occurrence of RTIs and overall mortality. These results have been also confirmed in an individual patient metanalysis reported elsewhere (D'Amico, 1998). The yield of the treatment expressed in terms of patients needed to be treated to prevent one infection and one death is substantial - five and 23 respectively - and compares very favourably with several interventions largely used in clinical practice. Though 8/16 trials used an identical regimen, including polymyxin, tobramycin and amphotericin as the topical combination and cefotaxime as the systemic component [Abele-Horn, 1997; Blair, 1991; Finch, 1991; Jacobs 1992a, 1992; Kerver, 1988; Palomar, 1997; Rocha, 1992; Stoutenbeek 1, 1996], this review does not allow a unique regimen to be recommended.The use of a prophylaxis testing topical antimicrobials is, on the other hand, not warranted by available data.
Results of this review should now be carefully considered by those intensivists who have been so far skeptical about the effectiveness of antibiotic prophylaxis. Insufficient data on cost-effectiveness and on antibiotic resistance should rather stimulate future research than prevent the adoption of a seemingly effective intervention. The impact of antibiotic prophylaxis on costs has been evaluated so far only rarely and, more importantly, in an improper way (the analysis being essentially based on comparisons of lengths of stay and computation of charges due to antibiotic use). A proper economic analysis is, on the other hand, likely to be difficult in a highly specialised setting, such as the ICU, where it is hard to quantify the relative contribution of single procedures and given the current lack of reliable data on resistance.

Implications for research

The number of RCTs on antibiotic prophylaxis so far conducted is substantial and provides sufficient statistical power to detect a moderate but humanly worthwhile effect of the treatment on mortality (SDD Group 1993). According to this systematic review, the protocol testing a combination of topical and systemic antibiotics should be the standard against which new treatments have to be tested. A logical next step for future trials would seem the comparison of this protocol against a regimen based on a systemic antimicrobial only; only six trials included in this review chose this as their study design. It is unlikely, however, that one or more even large conventional trials can satisfy the concerns of those afraid that antimicrobial resistance may occur as a consequence of widespread use of antibiotics. In order to produce a satisfactory answer to this dilemma, perhaps trials with a different design should be conceived.
Trials of this sort may be designed having the ICU, rather than individual patient, as the unit of randomisation and monitoring the occurrence of antibiotic resistance over a long period of time. One or more trials with these characteristics should be able to enrol a few thousands patients and should be designed in a very pragmatic fashion concentrating on outcomes such as mortality, resistance and costs. In the meantime a systematic analysis of the quality and reliability of existing data on resistance is an urgent priority to obtain a more comprehensive view of the yield of the treatment.

Potential conflict of interest

None

Acknowledgements

This systematic review would have not been possible without the continuous and enthusiastic support of most of the investigators of the trials. They should all be considered as co-authors of this paper as they collaborated in the different phases of this review by providing information on the design and conduct of their studies, checking the accuracy of the data before the final analysis, attending a meeting where preliminary results were presented and, finally, reviewing earlier drafts of the manuscript.
They names are listed below (in alphabetical order): M Abele-Horn (Ludwig-Maximilians-Universitat, Munich, Germany); SJA Aerdts (Sophia Hospital, Zwolle, The Netherlands); P Blair, B J Rowlands, H Webb and K Lowry (Royal Victoria Hospital, Belfast, Northern Ireland); JP Boland, D Sadler, A Stewart and J Pollock (Health Science Center Charlestone, West Virginia University, West Virginia, USA); C Brun-Buisson (Hopital Henry Mondor, Creteil, France); FB Cerra (University of Minnesota Hospital and Clinic, Minneapolis, USA); FR Cockerill and RL Thompson (Mayo Clinic, Rochester, Minnesota, USA); M Ferrer and A Torres (Servei de Pneumologia, Hospital Clinic, Barcelona, Spain); RG Finch, P Tomlinson and G Rocker (Nottingham City Hospital, Nottingham, United Kingdom); H Gastinne (on behalf of the French study group on Selective Decontamination of the Digestive Tract - France); P Gaussorgues (Hopital Eduoard Herriot, Lyon, France); B Georges (Hopital de Rangueil, Toulouse, France); JMJ Hammond, PD Potgieter (Groote Schuur Hospital, Cape Town, South Africa); S Jacobs (University Hospital of Wales, Cardiff, United Kingdom); S Jacobs and M Zuleika (Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia); AJH Kerver (Sint Franciskus Hospital, Rotterdam, Utrecht, The Netherlands); AM Korinek (Hopital Pitie-Salpetriere, Paris, France); AN Laggner (Vienna General Hospital, Vienna, Austria); FP Lenhart (University of Munich, Germany); W Lingnau (Leopold-Franzens-Universitat Innsbruck, Innsbruck, Austria); A Martinez-Pellus and J Rodriguez-Roldan (University Hospital Virgen de la Arrixaca, El Palmar, Murcia, Spain); M Palomar (Hospital Vall d'Hebron, Barcelona, Spain); J Pugin and P Suter (University Hospital, Geneva, Switzerland); C Martin, B Quinio and J Albanese (Hopital Nord, Marseilles, France); LA Rocha (Hospital Juan Canalejo, La Coruna, Spain); M Sanchez-Garcia (Hospital PPE Asturias, Alcala de Henares, Spain); CP Stoutenbeek (Academisch Ziekenhuis, Universiteit van Amsterdam, Amsterdam, The Netherlands); C Ulrich and J E Harinck-De Weerd (Westeinde Hospital, The Hague, The Netherlands); K Unertl (Klinikum Grosshadern, Munich, Germany); J Verhaegen and C Verwaest (University Hospital Gasthuisberg, Leuven, Belgium); J Wiener (Michael Reese Hospital, Chicago, USA); R Winter (Queens Medical Centre University Hospital, Nottingham, United Kingdom).

We acknowledge the contribution of the Steering Committee of this project composed by (in alphabetic order): J. Carlet (Hopital Saint-Joseph, Paris, France); DJ Cook (McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada); M Langer (Ospedale Maggiore Policlinico IRCCS, Milano, Italy); P Loirat (C.M.C. FOCH Suresnes, Paris, France); R V Saene (Alder Hey Children's Hospital, Liverpool, UK) .

We thank E Telaro (Mario Negri Institute, Milano, Italy) for her useful help in the preparation of this manuscript; J Lipman 1994, J Scribante (Baragwanath Hospital, Bertsham, Rebublic of South Africa), R Williams and N Rolando (King's College Hospital, London, United Kingdom) for providing individual patient data of their trials.

This was initiated at the request of the French Society of Intensive Care in preparation for the consensus conference on Selective Decontamination of the Digestive Tract (Paris, December 1991). It was then continued and updated between 1991 and 1993 through resources made available from the Mario Negri Institute, Milan, Italy
The collection of individual patient data carried out between 1993 and 1994 was possible through funds made available from Hoechst Italy. The sponsor had no control on the protocol preparation, data analysis and manuscript review and its support was sought after the decision of undertaking the review by the Authors.

Characteristics of included studies

Study Abele-Horn
MethodsRandomised study blinded for radiologic diagnosis
Randomisation method: list block randomised assignments maintained by the main investigator. Open.
Accrual period: not available
ParticipantsEligibility 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
InterventionsGroup 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
OutcomesRespiratory 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 > 3x10^4 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 >10^4 CFU/ml and granulocytes >10/field

Mortality: in ICU
NotesData about 37 excluded patients are not available
Allocation concealmentD
Study Aerdts
MethodsRandomised 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
ParticipantsEligibility 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
Percentage of ventilated patients: 100%
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%
Percentage of patients treated with systemic antibiotic therapy (not stated by protocol) in the first 3 days: Treatment =35% CTR=80%
Stress ulcer prophylaxis applied: antiacids until enteral feeding was possible
InterventionsGroup 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 metronidazole 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.
OutcomesRespiratory 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
NotesThe 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
Allocation concealmentD
Study Blair
MethodsRandomised study
Randomisation method: sealed envelopes. Blind
Accrual period: Sept. 1988 - Jan 1990
ParticipantsEligibility 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

Patients enrolled in the study: 331
Percentage of ventilated patients: 93%
Length of stay in ICU, median: 5 days
Type of admission diagnosis: medical=14% surgical scheduled=33% surgical unscheduled=13% trauma=40%
Severity score on admission: APACHE II mean=14.4, ISS mean=24.8
Percentage of immunocompromised patients: 1.8%
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
InterventionsGroup 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
OutcomesRespiratory infections (pneumonia acquired after 48 hrs); Diagnosis of infection was based on the fulfillment of Criteria I or Criteria II.
Criteria I: temperature >38.5°C on two separate occasion, WBC >12x10^9/l or <4x10^9 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
NotesPersonal 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
Allocation concealmentD
Study Boland
MethodsRandomised, placebo-controlled, double-blind study
Randomisation method: computer generated randomisation directed by the pharmacy department. Blind
Accrual period: Apr 89-Mar 91
ParticipantsEligibility 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

Patients enrolled in the study: 64
Percentage of ventilated patients: 100%
Length of stay in ICU, median: 8 days
Type of admission diagnosis: trauma=100%
Severity score on admission: APACHE II mean=16.8, ISS not available
Percentage of immunocompromised patients: 0%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=0% CTR=0%
Stress ulcer prophylaxis applied: H2-blockers or sucralfate (78%).
InterventionsGroup A, CTR:
-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
OutcomesRespiratory 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
NotesPersonal contact with the main investigator provided data about 23 patients who were excluded from the published paper (20 early extubation, 3 early death); these data are considered in analysis
Allocation concealmentD
Study Brun-Buisson
MethodsRandomised trial
Randomisation method: odd and even birth year technique. Open
Accrual period: Apr 87-May 87
ParticipantsEligibility 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

Patients enrolled in the study: 133
Percentage of ventilated patients: 59%
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%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=41% CTR=53%
Stress ulcer prophylaxis applied: none
InterventionsGroup A, Treatment:
-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
OutcomesRespiratory infections (pneumonia acquired in the ICU or within 48 hrs from discharge).
Diagnosis of infection was based on:
purulent sputum or tracheal aspirate associated with a new and persistent pulmonary infiltrate on x-Ray and the culture of at least 10^9 CFU/l from a protected wedged catheter sample of bronchial aspirate, temperature >38°C, WBC >10x10^9/l

Mortality: in ICU
NotesSetting: acute and intermediate areas of a medical ICU
Personal contact with the main investigator provided data about 47 patients who were excluded from the published paper (7 early death, 1 tranferring, 39 other); these data are considered in analysis
Allocation concealmentD
Study Cerra
MethodsRandomised, placebo-controlled, double-blind study
Randomisation method: sealed envelopes. Blind
Accrual period: Sept. 1988 - Jan 1990
ParticipantsEligibility 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, gastrointestinal leak or fistula

Patients enrolled in the study: 48
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
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: not available
Stress ulcer prophylaxis applied: not available
InterventionsGroup A, Treatment:
-Norfloxacin 500mg x3, Nystatin 1 milion U x 4 applied enterally until discharge

Group B, CTR:
-Placebo
OutcomesRespiratory infections: not evaluable

Mortality
NotesPersonal contact with the main investigator provided data about 2 patients who were excluded from the published paper for short length of stay); these data are considered in analysis
Allocation concealmentD
Study Cockerill
MethodsRandomised study blinded for respiratory diagnosis. Intention to treat
Randomisation method: randomisation table at a remote site in the pharmacy. Blind
Accrual period: 1986-1989
ParticipantsEligibility 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

Patients enrolled in the study: 150
Percentage of ventilated patients: 85%
ICU length of stay, median: 4.5 days
Type of admission diagnosis: medical=18% surgical scheduled=27% surgical unscheduled=21% trauma=34%
Severity score on admission: APACHE II mean=19.4, ISS mean 24.3
Percentage of immunocompromised patients: 4%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=75% CTR=80%
Stress ulcer prophylaxis applied: H2-blockers (80%)
InterventionsGroup A, CTR:
- 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
OutcomesRespiratory 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

Mortality: in hospital
Notes 
Allocation concealmentD
Study Ferrer
MethodsRandomised, placebo-controlled, double-blind study
Randomisation method: computer generated table. Open
Accrual period: Jan 91-Mar 92
ParticipantsEligibility 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%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 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
InterventionsGroup A, Treatment:
-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
OutcomesRespiratory 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>=12x10^9 WBC/l or leukopenia<=4x10^9

Mortality: in ICU
NotesPersonal 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
Allocation concealmentD
Study Finch
MethodsRandomised study
Randomisation method: sealed envelopes. Randomisation series made available to the hospital Pharmacy only. Blind
Accrual period: Aug 87-Sept 89
ParticipantsEligibility criteria: all patients whose length of stay was > 60 hrs, age >16 yrs
Exclusion criteria: none

Number of patients enrolled in the study: 49
Percentage of ventilated patients: not available
Length of stay in ICU: not available
Type of admission diagnosis: medical 59% surgical scheduled 27% surgical unscheduled 10% trauma=4%
Severity score on admission: SAPS mean=10.5, ISS not available
Percentage of immunocompromised patients: 22%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=58% CTR=68%
Stress ulcer prophylaxis applied: not available
InterventionsGroup A, Treatment:
-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
OutcomesRespiratory 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 > 10^5 CFU, diagnosis of septicemia, clinical signs of pulmonary infections (fever, leukocytosis and appropriate radiological findings)

Mortality: in ICU
NotesPersonal 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
Allocation concealmentD
Study Gastinne
MethodsRandomised, 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
ParticipantsEligibility 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

Number of patients enrolled in the study: 445
Percentage of ventilated patients: 100%
Length of stay in ICU, median: 12days
Type of admission diagnosis: medical 72% surgical scheduled 3% surgical unscheduled 10% trauma=15%
Severity score on admission: SAPS mean=13.5, ISS not available GCS mean=11.7
Percentage of immunocompromised patients: 18%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=89% CTR=84%
Stress ulcer prophylaxis applied: sucralfate (43% pts), H2-blockers (13% pts)
InterventionsGroup A, CTR:
-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
OutcomesRespiratory infections (pneumonia diagnosed within 48 hrs and acquired):
Diagnosis of infection was based on:
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.

Mortality: in hospital
Notes 
Allocation concealmentD
Study Gaussorgues
MethodsRandomised study. Intention to treat
Randomisation method: odd-even numbers. Open
Accrual period: Sept.88-Sept.89
ParticipantsEligibility criteria: all patients admitted to the ICU, who required mechanical ventilation and inotropic drugs for hemodinamic reasons
Exclusion criteria: neutropenia

Patients enrolled in the study: 118
Percentage of ventilated patients: 100%
ICU length of stay: not available
Type of admission diagnosis: medical=83% surgical scheduled=17% (all patients were infected on admission)
Severity score on admission: SAPS mean=17.5
Percentage of immunocompromised patients: not available
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=100% CTR=100%
Stress ulcer prophylaxis applied: sucralfate 4 g to all patients
InterventionsGroup A, Treatment:
-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
OutcomesRespiratory infections: not evaluable

Mortality: in ICU
NotesAll patients were infected on admission.
Data about respiratory infections are not provided
Allocation concealmentD
Study Georges
MethodsRandomised, placebo-controlled study
Randomisation method: sealed envelopes. Blind
Accrual period: Jun 1990-April 1992
ParticipantsEligibility 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 immunocompromised patients: 0%
Percentage of patients treated with systemic antibiotic therapy in the first 3 days: almost 100%
Stress ulcer prophylaxis: H2-blockers
InterventionsGroup 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
OutcomesRespiratory infections (acquired pneumonia)
Diagnosis of infection was based on:
Fever >38.5 °C, leukocytosis > 12000/mm3, new infiltrates in the chest X-rays, purulent pulmonary secretions, positive bacteriologic findings (>10^3 CFU/ml) obtained through a protected catheter

Mortality: in ICU and hospital
NotesAntibiotic prophylaxis was free and almost all patients of both groups were treated with systemic antibiotics.
74 potentially eligible patients were excluded from analysis; it is not evident if this happened before or after randomisation; these data are not available
Allocation concealmentD
Study Hammond
MethodsRandomised, placebo-controlled, double-blind study
Randomisation method: computer generated random numbers. Open
Accrual period: Jan 89-Dec 90
ParticipantsEligibility 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

Number of patients enrolled in the study: 322
Percentage of ventilated patients: 100%
Length of stay in ICU, median: 11 days
Type of admission diagnosis: medical 55% surgical scheduled 3% surgical unscheduled 11% trauma=31%
Severity score on admission: APACHE II mean=13.9, ISS mean=28.7
Percentage of immunocompromised patients: 0.8%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=54% CTR=58%
Stress ulcer prophylaxis applied: none, H2-blockers only to high risk patients
InterventionsGroup A, Treatment:
-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
OutcomesRespiratory 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>10^10/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

Mortality: in hospital
NotesPersonal contact with the main investigator provided data on 82 patients who were excluded and separately considered in the published paper (78 short stay, 3 protocol violation, 1 unknown); these data are considered in the analysis
Allocation concealmentD
Study Jacobs 1992a
MethodsRandomised study
Randomisation method: sealed envelopes. Blind
Accrual period: Jul 89-Aug 90
ParticipantsEligibility criteria: expected stay in ICU > 3 days
Exclusion criteria: none

Patients enrolled in the study: 91
Percentage of ventilated patients: 100%
ICU length of stay, median: unknown
Type of admission diagnosis: medical=25% surgical=57% trauma=18% (high percentage of neurologic and neurosurgical patients 52%)
Severity score on admission: APACHE II mean=17.5, ISS not available
Percentage of immunocompromised patients: unknown
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 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
InterventionsGroup A,Treatment:
-Polymyxin E 100mg, Tobramycin 80 mg, Amphotericin B 500 mg applied orally and enterally 4 times a day until extubation
-Cefotaxime 50 mg/kg/day iv x 4 days

Group B, CTR:
-No prophylaxis
OutcomesRespiratory infections (acquired pneumonia):
Diagnosis of infection was based on:
alveolar infiltrates on 2 or more chest X-rays, moderate or copious purulent tracheal aspirate, rectal temperature >38.4°C, leucocytosis >13x10^9/l, a heavy growth of organisms from tracheal aspirate with a high polymorphonuclear leucocytes/epithelial cell ratio

Mortality
NotesAlmost 100% of patients received systemic antibiotic therapy on admission.
Personal contact with the main investigator provided data about 12 patients who were excluded from the published paper (11 short stay in ICU, 1 HIV+); these data are considered in the analysis
Allocation concealmentD
Study Jacobs 1992b
MethodsRandomised study
Randomisation method: sealed envelopes. blind
Accrual period: May 94-Mar 95
ParticipantsEligibility criteria: expected need of ventilation for at least 3 days
Exclusion criteria: Death or extubation before 3 days

Patients enrolled in the study: 70
Percentage of ventilated patients: 100%
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
Percentage of immunocompromised patients: 7.1%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=77% CTR=66%
Stress ulcer prophylaxis applied: none
InterventionsGroup A, Treatment:
-Polymyxin E 100mg, Gentamycin, Amphotericin B 500 mg

Group B, CTR:
-No prophylaxis
OutcomesRespiratory infections (pneumonia acquired after 48hrs):
diagnosis was based on Clinical Pulmonary Infection Score as defined by Pugin 1991

Mortality: follow up
NotesPersonal 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
Allocation concealmentD
Study Kerver
MethodsRandomised study
Randomisation method: odd/even numbers. Open
Accrual period: Jan 85-May 86
ParticipantsEligibility criteria: all patients admitted to the surgical ICU who required care >5 days
Exclusion criteria: none

Patients enrolled in the study: 96
Percentage of ventilated patients: 100%
ICU length of stay, not available
Type of admission diagnosis: surgical=60% trauma = 28% other =12%
Severity score on admission: APACHE II mean=14.8, ISS not available
Percentage of immunocompromised patients: not available
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: about 85%
Stress ulcer prophylaxis applied: not available
InterventionsGroup A, Treatment:
- 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
OutcomesRespiratory 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 >10x10^3 or <4x10^3/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 
Allocation concealmentD
Study Korinek
MethodsRandomised, 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
ParticipantsEligibility criteria: all comatose patients with emergency admission to two neurosurgical ICUs and intubated 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

Number of patients enrolled in the study: 191
Percentage of ventilated patients: 100%
Length of stay in ICU, mean: 26 days
Type of admission diagnosis: surgical scheduled 11% surgical unscheduled 39% trauma 50%
Severity score on admission: SAPS mean=10.9, ISS not available
Percentage of immunocompromised patients: 0%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=0% CTR=0%
Stress ulcer prophylaxis applied: sucralfate (32%), antiacids (14%), H2-blockers (20%) until enteral feeding was started
InterventionsGroup A, Treatment:
-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 treatment occurred and at the time of patient's extubation
OutcomesRespiratory infections (pneumonia acquired after 5 days)
Diagnosis of infection was based on:
fever >38.5°C, leukocytosis > 12,000 cells/mm3, purulent sputum, new and persistent infiltrates on chest X-ray and a culture of >10^3 CFU/ml obtained with either brush or plugged telescoping catheter

Mortality: in ICU
NotesSetting: 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 considered in the analysis
Allocation concealmentD
Study Laggner
MethodsRandomised, placebo-controlled, double-blind study
Randomisation method: computer generated randomisation in time blocks. Open
Accrual period: Aug 87-Nov 90
ParticipantsEligibility 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
Percentage of ventilated patients: 100%
Length of stay in ICU, mean: 28.8 days
Type of admission diagnosis: medical 88% surgical scheduled 9% surgical unscheduled 1% trauma=2%
Severity score on admission: APACHE II mean=23, ISS not available
Percentage of immunocompromised patients: 15%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: 100%
Stress ulcer prophylaxis applied: sucralfate
InterventionsGroup A, Treatment:
-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
OutcomesRespiratory infections (acquired pneumonia):
Diagnosis of infection was based on:
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.
NotesData about 21 patients who were excluded from the published paper (18 short mechanical ventilation, 3 early enteral nutrition) are not available
Allocation concealmentD
Study Lenhart
MethodsRandomised, placebo-controlled, double-blind, double centre study
Randomisation method: unknown
Accrual period: Apr 89-Mar 91
ParticipantsEligibility 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
Percentage of ventilated patients: not available
ICU length of stay, not available
Type of admission diagnosis: not available
Severity score on admission: APACHE II mean=20, 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 to all patients
InterventionsGroup A, Treatment:
-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
OutcomesRespiratory infections: not evaluable

Mortality
NotesData about 19 patients excluded from the published paper are not available.
Data about respiratory infections are not evaluable
Allocation concealmentD
Study Lingnau 1997a
MethodsRandomised, 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
ParticipantsEligibility 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)
Percentage of ventilated patients: 100%
ICU length of stay, mean: 20 days
Type of admission diagnosis: trauma=100%
Severity score on admission: APACHE II mean=15.6, ISS mean=35.2
Percentage of immunocompromised patients: 0%
Percentage of patients treated with systemic antibiotic therapy (not stated by protocol) in the first 3 days: treatment 1=2% treatment 2=2% CTR=6%
Stress ulcer prophylaxis applied: free
InterventionsGroup 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
OutcomesRespiratory infections (acquired pneumonia):
Diagnosis of infection was based on:
concomitant occurence of purulent sputum, positive cultures of bronchial secretions and deterioration of lung function

Mortality: in ICU
NotesThis 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)
Allocation concealmentD
Study Lingnau 1997b
Methodssee Lingnau a
Participantssee Lingnau a
Only two groups of patients, group B and C, are considered in this comparison, totalling 267 patients
InterventionsGroup 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
Outcomessee Lingnau a
Notessee Lingnau a
Allocation concealmentD
Study Palomar
MethodsRandomised, 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)
Randomisation method: sealed envelopes. Blind
Accrual period: Jul 89-Aug 91
ParticipantsEligibility 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

Number of patients enrolled in the study: 97
Percentage of ventilated patients: 100%
Length of stay in ICU, median 10 days
Type of admission diagnosis: medical 40% surgical 10% trauma 50%
Severity score on admission: APACHE II mean=16.8, ISS not available
Percentage of immunocompromised patients: 0%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=0% CTR=6%
Stress ulcer prophylaxis applied: sucralfate to one control group (excluded from metanalysis), antiacids or H2-blockers to the two other groups
InterventionsGroup 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
-Cefotaxime 1gx3 iv for the first 4 days

Group C*, CTR 2:
-Cefotaxime 1gx3 iv for the first 4 days
-Sucralfate

* This group was excluded from analysis because it was the only one receiving sucralfate
OutcomesRespiratory 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
NotesPersonal 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 considered in the analysis
Allocation concealmentD
Study Pugin
MethodsRandomised, placebo-controlled, double-blind study
Randomisation method: sealed envelopes. Blind
Accrual period: Apr 89-Nov 89
ParticipantsEligibility 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

Number of patients enrolled in the study: 79
Percentage of ventilated patients: 100%
Length of stay in ICU, mean 13.8 days
Type of admission diagnosis: medical 11% surgical scheduled 11% surgical unscheduled 22% trauma 56%
Severity score on admission: APACHE II mean=15.2, ISS not available
Percentage of immunocompromised patients: not available
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=46% CTR=53%
Stress ulcer prophylaxis applied: sucralfate (61%), ranitidine (11%)
InterventionsGroup A, Treatment:
-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
OutcomesRespiratory infections (pneumonia acquired after 48 hrs): Pneumonia are defined by the "clinical pulmonary 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)

Mortality: in hospital
NotesPersonal 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
Allocation concealmentD
Study Quinio
MethodsRandomised, 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
ParticipantsEligibility 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

Number of patients enrolled in the study: 149
Percentage of ventilated patients: 100%
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
Percentage of immunocompromised patients: 0%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=35% CTR=26%
Stress ulcer prophylaxis applied: sucralfate until enteral feeding was effective, H2-blockers in high risk patients
InterventionsGroup A,Treatment:
-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
OutcomesRespiratory 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 
Allocation concealmentD
Study Rocha
MethodsRandomised, placebo-controlled, double-blind study
Randomisation method: made by the Pharmacy's service according to computer generated random numbers. Blind
Accrual period: Sept 89-Oct 90
ParticipantsEligibility 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

Number of patients enrolled in the study: 151
Percentage of ventilated patients: 100%
Length of stay in ICU, median 8 days
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%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=0% CTR=0%
Stress ulcer prophylaxis applied: H2-blockers and antiacids
InterventionsGroup A, Treatment:
-Polymyxin E 100mg, Tobramycin 80mg, Amphotericin B 500 mg applied enterally and, as a 2% paste, to the oropharynx 4 times a day
-Cefotaxime 6g/day iv for the first 4 days

Group B, CTR:
-Placebo
-No systemic prophylaxis
OutcomesRespiratory infections (acquired pneumonia):
Diagnosis of infection was based on:
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
NotesPersonal 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
Allocation concealmentD
Study Rodriguez-Roldan
MethodsRandomised, placebo-controlled, double-blind, dual-center study
Randomisation method: odd and even numbers. Open
Accrual period: Jun 88-Dec 88
ParticipantsEligibility 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

Number of patients enrolled in the study: 31
Percentage of ventilated patients: 100%
Length of stay in ICU, median 13.5 days
Type of admission diagnosis: medical 39% surgical scheduled 16% surgical unscheduled 3% trauma 42%
Severity score on admission: APACHE II mean=17.1, ISS not available
Percentage of immunocompromised patients: 0%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=36% CTR=35%
Stress ulcer prophylaxis applied: sucralfate or alkaline agents plus ranitidine according to a randomised open protocol
InterventionsGroup A, Treatment:
-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
OutcomesRespiratory 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, increased alveolar-arterial oxygen gradient;
B) Radiologic criteria: new and persistent infiltrate;
C) Bacteriologic criteria: quantitative culture of tracheal aspirates > 10^3 CFU/ml (in 6 patients either bronchoscopy or a telescoped catheter were used to obtain the sample)

Mortality: in ICU
NotesPersonal contact with the main investigator provided data about 3 patients who were excluded from the published paper (2 early death, 1 other); these data are considered in the analysis
Allocation concealmentD
Study Sanchez-Garcia
MethodsRandomised, placebo-controlled, double-blind, multicentric (5 ICUs) study
Randomisation method: sealed envelopes. Blind
Accrual period: not available
ParticipantsEligibility 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 transplantation, absence or contraindication to nasogastric tube

Number of patients enrolled in the study: 271
Percentage of ventilated patients: 100%
Length of stay in ICU, median 13 days
Type of admission diagnosis: medical 70% surgical scheduled 3% surgical unscheduled 9% trauma 18%
Severity score on admission: APACHE II mean=26.6, ISS not available
Percentage of immunocompromised patients: 4.4%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=70% CTR=69%
Stress ulcer prophylaxis applied: each group was randomised to receive either sucralfate or H2-blockers
InterventionsGroup A, Treatment:
-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
OutcomesRespiratory infections (early and late acquired pneumonia):
Diagnosis of infection was based on:
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
NotesPersonal contact with the main investigator provided data about 45 patients who were excluded from the published paper (12 early extubation, 12 early death, 17 protocol violation, 2 transferring, 2 other); these data are considered in the analysis
Allocation concealmentD
Study Stoutenbeek 1
MethodsRandomised, placebo-controlled, double-blind study
Randomisation method: closed envelope method (the code was known by the pharmacist only). Blind
Accrual period: Nov 84 - Aug 86
ParticipantsEligibility 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

Number of patients enrolled in the study: 91
Percentage of ventilated patients: 100%
Length of stay in ICU, mean=15 days
Type of admission diagnosis: trauma 100%
Severity score on admission: APACHE II mean=10.6, HTI-ISS mean=35.1
Percentage of immunocompromised patients: 0%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=0% CTR=0%
Stress ulcer prophylaxis applied: none except for patients with history of preexisting ulcer or on H2-blockers
InterventionsGroup A, Treatment:
-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
OutcomesRespiratory infections (tracheobronchitis and pneumonia - early and late infections)
Diagnosis of infection was based on clinical criteria: temperature >38.5°C, WBC >12,5x10^9/l or leukopenia <4x10^9/l, purulent secretions or X-ray changes and significant growth of bacteria

Mortality: in ICU
NotesData about 32 patients who were initially excluded (25 early extubation, 4 early death, 3 other) are considered in the analysis
Allocation concealmentD
Study Stoutenbeek 2
MethodsRandomised, 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
ParticipantsEligibility criteria: patients admitted within 24 hrs after a blunt trauma with an HTI-ISS >=16, necessitating 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
Percentage of ventilated patients: 100%
Length of stay in ICU, median=11 days
Type of admission diagnosis: trauma 100%
Severity score on admission: APACHE II mean=12.6, HTI-ISS mean=35.0
Percentage of immunocompromised patients: 0%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=46% CTR=88%
Stress ulcer prophylaxis applied: sucralfate, H2-blockers, antiacids; sucralfate was not allowed in the treatment group
InterventionsGroup A, Treatment:
-Polymyxin E, Tobramycin, Amphotericin B applied orally, enterally and vaginally 4 times a day until discharge
-Cefotaxime 50 mg/kg/day iv x 4 days

Group B, CTR:
-Standard antibiotic prophylaxis (no fluoroquinolones)
OutcomesRespiratory 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)
NotesData on 3 patients (protocol violation) are not available. Mortality datum about one more patient is lacking.
Allocation concealmentD
Study Ulrich
MethodsRandomised, placebo-controlled study
Randomisation method: sealed envelopes containing a random code for clusters of 4 patients. Blind
Accrual period: Oct 86-Sep 87
ParticipantsEligibility 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

Number of patients enrolled in the study: 112
Percentage of ventilated patients: about 80%
Length of stay in ICU, median=10 days
Type of admission diagnosis: medical 34% surgical scheduled 19% surgical unscheduled 31% trauma 16%
Severity score on admission: SAPS mean=11.7, ISS mean=36.9
Percentage of immunocompromised patients: 3%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=83% CTR=81%
Stress ulcer prophylaxis applied: not available
InterventionsGroup A,Treatment:
-Polymyxin E 100mg, Norfloxacin 50mg, Amphotericin B 500 mg, applied enterally and, as a 2% paste, to the oropharynx 4 times a day
-Trimethoprim 500mg iv

Group B, CTR:
-Placebo
OutcomesRespiratory infections (acquired pneumonia):
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
NotesPersonal contact with the main investigator provided data about 12 patients who were excluded from the published paper (early death); these data are considered in the analysis
Allocation concealmentD
Study Unertl
MethodsRandomised study, blinded for radiologic diagnosis
Randomisation method: blocked randomisation scheme and the sealed envelope technique. Blind
Accrual period: May 84 - Jan 85
ParticipantsEligibility 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

Number of patients enrolled in the study: 39
Percentage of ventilated patients: 100%
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)
Percentage of immunocompromised patients: not available
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: not available
Stress ulcer prophylaxis applied: H2-blockers to all patients and antiacids if pH <4
InterventionsGroup A, Treatment:
-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
OutcomesRespiratory infections (acquired pneumonia):
Diagnosis of infection was based on:
new 'definite' infiltrate on chest X-ray together with increasing amounts of purulent tracheobronchial secretion containing >3x10^4 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 
Allocation concealmentD
Study Verwaest 1997a
MethodsRandomised 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
ParticipantsEligibility 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 bacteriological 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)
Percentage of ventilated patients: 100%
Length of stay in ICU, mean=19.6 days
Type of admission diagnosis: medical 10%, surgical 67% trauma 23%
Severity score on admission: APACHE II mean=18.1, ISS not available
Percentage of immunocompromised patients: not available
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment 1=34% treatment 2=31% CTR=34%
Stress ulcer prophylaxis applied: sucralfate 2g x4
InterventionsGroup A, CTR:
- 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
OutcomesRespiratory infections (pneumonia acquired after 48 hrs):
Diagnosis of infection was based on:
Fever >38.5°C, leukocytosis >10,000 cells/mcl, luxuriant growth of potentially pathogenic micro-organisms in culture of bronchial aspirate, new and persistent infiltrate on chest X-ray

Mortality: in ICU
NotesThis 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
Allocation concealmentD
Study Verwaest 1997b
Methodssee Verwaest a
Participantssee Verwaest a
Only two groups of pts, group A and C, are considered in this comparison, totalling 440 pts
InterventionsGroup A, CTR:
- No prophylaxis, antibiotic therapy was used only if an infection was suspected

Group C, Treatment: 2:
- Polymyxin E 50mg, Tobramycin 80 mg, Amphotericin B 500 mg applied enterally and, as a 2% paste, to the oropharynx 4 times a day until discharge
- Cefotaxime 1g x4 iv x 4 days
Outcomessee Verwaest a
Notessee Verwaest a
Allocation concealmentD
Study Wiener
MethodsRandomised, placebo-controlled, double-blind study
Randomisation method: random number table in blocks of six patients. Open
Accrual period: 8 months
ParticipantsEligibility 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
Percentage of ventilated patients: 100%
Length of stay in ICU, mean: 11.3 days
Type of admission diagnosis: not available
Severity score on admission: APACHE II mean=27.2, ISS not available
Percentage of immunocompromised patients: >5%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=93% CTR=81%
Stress ulcer prophylaxis applied: H2-blockers to most pts
InterventionsGroup A, Treatment:
-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
OutcomesRespiratory 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 > 10^3 bacteria from a quantitative culture of lower respiratory tract secretions obtained with a blind protected catheter

Mortality: in ICU
Notes60 patients were excluded after randomisation; data are not available
Allocation concealmentD
Study Winter
MethodsRandomised study
Randomisation method: sealed envelopes based on a computer generated table of random numbers. Blind
Accrual period: Jul 88-May 90
ParticipantsEligibility criteria: patients likely to remain in the ICU for at least 48 hrs
Exclusion criteria: allergy to the antibiotics used, age >85yrs, pregnancy

Patients enrolled in the study: 183
Percentage of ventilated patients: 92%
Length of stay in ICU, median= 4 days
Type of admission diagnosis: medical 40% surgical scheduled 10% surgical unscheduled 37% trauma 13%
Severity score on admission: APACHE II mean=15.3, ISS mean= 26.2
Percentage of immunocompromised patients: 2.2%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first 3 days: treatment=47% CTR=64%
Stress ulcer prophylaxis applied: all CTR patients received sucralfate; H2-blockers were used in patients of both groups with peptic ulcer or pancreatitis
InterventionsGroup 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
OutcomesRespiratory infections (pneumonia acquired after 48 hrs): Diagnosis of infection was based on:
temperature >38.5°C two times in 24 hrs, WBC<4 or >12x10^9/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

Mortality: in hospital
NotesFew patients were excluded after randomisation; data are not available
Allocation concealmentD

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

StudyReason for exclusion
BionThe study included a selected population of patients undergoing liver transplant
FlahertyThe study included a selected population of cardiosurgical patients
HunefeldThe study was not properly randomised
Lipman 1994The study was not properly randomised
LuitenThe study included a selected population of patients affected by pancreatitis characterised by a low percentage of ICU admissions.
Martinez PAEThe study compared the effect of two different prophylactic regimens without a control group
Martinez-Pellus 2The study included a selected population of cardiosurgical patients
RolandoThe study included a selected population of patients with acute hepatic failure
SchardeyThe study included a selected population of patients undergoing gastric surgery and characterised by a low percentage of ICU admission.
TetterooThe study included a selected population of patients undergoing oesophageal resection and characterised by a short length of stay in ICU.

Graphs

Comparison 01. topical plus systemic vs no prophylaxis
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
overall mortality173581Peto Odds Ratio 95% CI0.80 [0.69, 0.93]
mortality according to randomisation  Peto Odds Ratio 95% CISubtotals only
mortality according to blinding of the studies  Peto Odds Ratio 95% CISubtotals only
RTIs162883Peto Odds Ratio 95% CI0.35 [0.29, 0.41]
RTIs according to randomisation  Peto Odds Ratio 95% CISubtotals only
RTIs according to blinding of the studies  Peto Odds Ratio 95% CISubtotals only
Figure 1.

Figure 1.

overall mortality

Figure 2.

Figure 2.

mortality according to randomisation

Figure 3.

Figure 3.

mortality according to blinding of the studies

Figure 4.

Figure 4.

RTIs

Figure 5.

Figure 5.

RTIs according to randomisation

Figure 6.

Figure 6.

RTIs according to blinding of the studies

Comparison 02. topical vs control
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
overall mortality182543Peto Odds Ratio 95% CI1.01 [0.84, 1.22]
mortality according to randomisation  Peto Odds Ratio 95% CISubtotals only
mortality according to blinding of the studies  Peto Odds Ratio 95% CISubtotals only
RTIs162377Peto Odds Ratio 95% CI0.56 [0.46, 0.68]
RTIs according to randomisation  Peto Odds Ratio 95% CISubtotals only
RTIs according to blinding of the studies  Peto Odds Ratio 95% CISubtotals only
Figure 7.

Figure 7.

overall mortality

Figure 8.

Figure 8.

mortality according to randomisation

Figure 9.

Figure 9.

mortality according to blinding of the studies

Figure 10.

Figure 10.

RTIs

Figure 11.

Figure 11.

RTIs according to randomisation

Figure 12.

Figure 12.

RTIs according to blinding of the studies

Comparison 03. Topical
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
Overall mortality182543Peto Odds Ratio 95% CI1.01 [0.84, 1.22]
Figure 13.

Figure 13.

Overall mortality

Comparison 04. Topical plus systemic
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
Overall mortality163493Peto Odds Ratio 95% CI0.80 [0.68, 0.93]
Figure 14.

Figure 14.

Overall mortality

Comparison 05. Topical
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
RTIs162356Peto Odds Ratio 95% CI0.57 [0.46, 0.69]
Figure 15.

Figure 15.

RTIs

Comparison 06. Topical plus systemic
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
RTIs152795Peto Odds Ratio 95% CI0.36 [0.30, 0.43]
Figure 16.

Figure 16.

RTIs

Comparison 07. Topical vs Systemic (subset-analysis)
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
Mortality203977Peto Odds Ratio 95% CI0.76 [0.65, 0.88]
Figure 17.

Figure 17.

Mortality

Comments and criticisms

Antibiotics for preventing respiratory tract infec

Summary

1. This enormous, admirable and important review is in many places
difficult to read because it is very densely written. It would be worth
trying to make it more reader-friendly.

2. The text and the tables of characteristics of included studies contain a
great number of abbreviations which will be unfamiliar to many readers.
Although most are explained where they first occur, it is tedious to have
to search the review to find the place, and I suspect that the search
facility does not include the tables. It would be useful to have a separate
list or glossary of abbreviations that can be accessed through 'Outline'.
That should be considered for all Cochrane reviews.

3. The review seems to assume that all SDD regimens are equivalent, and
that all systemic antibiotic prophylaxis regimens are equivalent. This may
well be correct, but it is a big assumption that deserves explicit
discussion. It would indeed be of interest in the conclusion to express a
view on future comparisons between different regimens: are they a waste of
time and effort? If not, what sorts of comparisons would be worth doing?

4. As a pharmacologist I have some interest in differences between drugs,
and I would like to have at least a summary of the evolution of the SDD
regimens and systemic prophylaxis regimens since the beginning. On what
have the changes of the last 10 or more years been based? Could you try to
separate scientific reasons from whim and fashion?

Author's reply

A glossary of terminology has been added at the bottom of the table of
included studies and abbreviations have been eliminated as far as possible.

In the method section we have added a statement that explains why we
decided to include all RCTs, regardless of the type of antibiotic used.

In the discussion section we have added a statement that tries to
clarify our view about the relative roles of different antibiotics. We do
not feel that a particular drug(s) can be claimed as more effective than
another but we have indicated which regimen has been the most commonly used
in various RCTs.

The English has been improved here and there as much as we could. The
paper still remains rather heavy to read and digest given the large number
of studies and the complexity of the issues discussed. However, we hope we
have improved it.

Finally, we could not comply with Andrew Herxheimer's suggestion of
discussing "temporal trends" in antibiotic used in RCTs over time as we
failed to identify such a trend. In the "Implications for research"
section, however, we clearly indicated which direction(s) future research
in the field should take.

Contributors

Andrew Herxheimer

Sources of support

External sources of support

  • No sources of support supplied

Internal sources of support

  • No sources of support supplied

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