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Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care

  1. Roberto D'Amico1,*,
  2. Silvia Pifferi2,
  3. Valter Torri3,
  4. Luca Brazzi4,
  5. Elena Parmelli5,
  6. Alessandro Liberati6,†

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 7 OCT 2009

Assessed as up-to-date: 13 MAR 2009

DOI: 10.1002/14651858.CD000022.pub3


How to Cite

D'Amico R, Pifferi S, Torri V, Brazzi L, Parmelli E, Liberati A. Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD000022. DOI: 10.1002/14651858.CD000022.pub3.

Author Information

  1. 1

    University of Modena and Reggio Emilia, Statistics Unit, Department of clinical and diagnostic medicine and public health, University of Modena and Reggio Emilia, Modena, Italy, Modena, Italy

  2. 2

    Policlinico San Matteo, Pavia, Milano, Italy

  3. 3

    Mario Negri Institute, Laboratorio di Epidemiologia Clinica, Milano, Milano, Italy

  4. 4

    Università degli Studi di Sassari, Dipartimento di Scienze Chirurgiche, Microchirurgiche e Mediche, Sassari, Italy

  5. 5

    University of Modena and Reggio Emilia, Department of Oncology, Hematology and Respiratory Diseases, Modena, Italy

  6. 6

    Mario Negri Institute for Pharmacological Research, Italian Cochrane Centre, Milan, Italy

  1. Deceased

*Roberto D'Amico, Statistics Unit, Department of clinical and diagnostic medicine and public health, University of Modena and Reggio Emilia, Modena, Italy, University of Modena and Reggio Emilia, Via del Pozzo 71, Modena, 41121, Italy. roberto.damico@unimore.it.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 7 OCT 2009

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Characteristics of included studies [ordered by study ID]
Abele-Horn 1997

MethodsRandomised controlled study
Blinding: Open
Randomisation method: list block randomised assignments maintained by the main investigator
Accrual period: not available


ParticipantsEligibility criteria: intubation within 24 hrs of admission, expected ventilation for at least four 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 patients were excluded leaving 88 patients 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 three days: not available
Stress ulcer prophylaxis applied: sucralfate 1 g x four to all patients


InterventionsGroup A, Treatment:
- polymyxin 100 mg, tobramycin 80 mg, amphotericin B 500 mg applied orally four times a day as a 2% paste during the ICU stay
- cefotaxime 2 g x 3 iv x three 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 > 3 x 104 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 > 104 CFU/ml and granulocytes > 10/field

Mortality: in ICU


NotesData about 37 excluded patients are not available


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Aerdts 1991

MethodsRandomised study with three arms (one treatment arm versus two control arms)
Blinding: outcome assessor
Randomisation method: sealed envelopes, permuted block method.
Accrual period: May 86 to Sept 87


ParticipantsEligibility criteria: expected ventilation for at least five 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 three 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 200 mg, norfloxacin 50 mg, amphotericin B 500 mg applied enterally four times a day and, as a 2% paste, to the oropharynx until extubation
- cefotaxime 500 mg x 3 iv x five 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 two 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 two control groups that are considered as a whole in the meta-analysis
Personal contact with the main investigator provided data about 32 patients who were excluded from the published paper (16 early extubation, seven early deaths, five protocol violation, three other, one unknown); these data are considered in the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Bergmans 2001

MethodsRandomised, placebo-controlled study.
Blinding: double blind.


ParticipantsElegibility criteria: intubation within 24 hrs of admission and need for mechanical ventilation with an expected duration > two hours
Esclusion criteria: age < 16 yrs.
Patients enrolled in the study: 226
Percentage of ventilated patients: 100%
ICU length of stay, median treatment group: 13 days; median control A group: 15 days, median control B group: 12 days
Type of admission diagnosis: Medical = 35%, Surgery = 39%, Trauma = 19%, Neurology = 6%, Other = 1%.
Severity score on admission: APACHE II mean = 21.4, ISS not available
Percentage of immuncompromised patients: 2%
Percentage of patients treated with systematic antibiotic therapy at admission:
Treatment: 47% CTR = 42%
Stress ulcer prophylaxis applied: Treatment = 61%
Control = 76%


InterventionsGroup A, Treatment:
Orabase with 2% gentamicin, 2% colistin and 2% vancomycin
Orabase was applied in the buccal cavities on a gloved finger every six hrs.
The application of Orabase was started within 24 h of intubation.
Application of treatment was limited to 21 days.

Group B, CTR1
no prophylaxis
- this group was studied in ICU in which there was the presence of patients receiving topical antimicrobial prophylaxis

Group C: CTR2
no prophylaxis
This control group was studied in ICU in which where no topical antimicrobial prophylaxis was used


OutcomesVentilator-associated pneumonia (VAP); diagnosis of VAP was established on the basis of positive quantitative cultures from BAL (cutoff point >= 104 colony-forming units [cfu]/ml) or PSB (cutoff point >= 103 cfu/ml), or a positive blood culture unrelated to another source of infection, or a positive culture from pleural fluid in the absence of previous pleural instrumentation.

Mortality: in hospital


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Blair 1991

MethodsRandomised study
Blinding: Open.
Randomisation method: sealed envelopes.
Accrual period: Sept. 1988 to Jan 1990


ParticipantsEligibility criteria: all admitted patients who do not fulfil the exclusion criteria
Exclusion criteria: patients discharged within 48 hrs of ICU admission; admission from CCU; patients expected to die after six hrs of ICU admission; patients with discharge anticipated within 48 hrs but remaining more than 48 hrs; drug overdose; security patients; age < 18 yrs; patients not randomised within six 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: five 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 three 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 100 mg, tobramycin 80 mg, amphotericin B 500 mg applied enterally four times a day and, as a 2% gel, to the oropharynx
- cefotaxime 50 mg/kg/day iv x four days


OutcomesRespiratory infections (pneumonia acquired after 48 hrs). Diagnosis of infection was based on the fulfilment of Criteria I or Criteria II.
Criteria I: temperature > 38.5°C on two separate occasion, WBC > 12 x 109/l or < 4 x 109 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 the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Boland 1991

MethodsRandomised, placebo-controlled study
Blinding: double blind
Randomisation method: computer generated randomisation directed by the pharmacy department
Accrual period: Apr 89 to Mar 91


ParticipantsEligibility criteria: all multiple traumatised patients, intubated at the time of admission and likely to stay intubated at least five days
Exclusion criteria: patients who did not remain intubated for five days

Patients enrolled in the study: 64
Percentage of ventilated patients: 100%
Length of stay in ICU, median: eight 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 three days: treatment = 0% CTR = 0%
Stress ulcer prophylaxis applied: H2-blockers or sucralfate (78%)


InterventionsGroup A, CTR:
- Placebo

Group B, Treatment:
- polymyxin 100 mg, tobramycin 80 mg, nystatin 1,600,000 units applied enterally four times a day and, as a 2% paste plus 60,000 units of nystatin, to the oropharynx until extubation or discharge
- cefotaxime 1 g x 3 iv for the first three 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 extubations, three early deaths); these data are considered in the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Brun-Buisson 1989

MethodsRandomised trial
Blinding: Open
Randomisation method: odd and even birth year technique
Accrual period: Apr 87 to 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 immunocompromised patients: 12.8%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first three days: treatment = 41% CTR = 53%
Stress ulcer prophylaxis applied: none


InterventionsGroup A, Treatment:
- polymyxin E 50 mg, neomycin 1 g, nalidixic acid 1 g, applied orally and enterally four 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 109 CFU/l from a protected wedged catheter sample of bronchial aspirate, temperature > 38°C, WBC > 10 x 109

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 (seven early deaths, one transferred, 39 other); these data are considered in the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)High riskC - Inadequate

Camus 2005

MethodsRandomised trial
Blinding: double
Randomisation method: performed by computer
Accrual period: April 1996 to October 1998


ParticipantsElegibility criteria: adults intubated for < 48 hrs and likely to require mechanical ventilation for > 48 hrs
Exclusion criteria: patients with SAPS II > 80 and life expectancy of < 48 hrs resulting from brain death of a palliative treatment, a polymorphonuclear count of < 500 cells/mm3, severe diarrhoea and anyone who had received either a prior decontamination regimen or was already participating in another ongoing clinical trial.
Patients enrolled: 256
Pecentage of ventilated patients: not reported
Length of stay in ICU: not reported
Type of admission diagnosis: home/emergency department = 43%, hospital ward = 57%
Severity score on admission: median SAPS II = 46
Percentage of immunocompromised patients: 3.9%
Percentage of patients treated with systemic antibiotic therapy (not stated in protocol) in the first three days: none
Stress ulcer prophylaxis applied: not reported


InterventionsGroup A - Treatment: solution containing 15 mg/ml polymyxin E and 10 mg/ml tobramycin
Group B - Control: placebo


OutcomesRespiratory infections: acquired infections
Mortality: in ICU


NotesThe study is a four arm, 2 x 2 factorial design. In this review we considered only two arms comparing SDD regimen versus placebo


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Cerra 1992

MethodsRandomised, placebo-controlled study
Blinding: double blind
Randomisation method: sealed envelopes
Accrual period: Sept 1988 to Jan 1990


ParticipantsEligibility criteria: admission within 48 hrs from surgery, trauma or other acute event, expected stay at least five days, hypermetabolism (VO2 > 140 ml/m2 or urinary nitrogen excretion > 10 g/day) without progressive MOSF (normal transaminases, stable bilirubin 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 immunocompromised patients: not available
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first three days: not available
Stress ulcer prophylaxis applied: not available


InterventionsGroup A, Treatment:
- norfloxacin 500 mg x 3, nystatin one million U x 4 applied enterally until discharge

Group B, CTR:
- Placebo


OutcomesRespiratory infections: not possible to evaluate

Mortality


NotesPersonal contact with the main investigator provided data about two patients who were excluded from the published paper for short length of stay); these data are considered in the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Cockerill 1992

MethodsRandomised study. Intention-to-treat
Blinding: outcome assessor
Randomisation method: randomisation table at a remote site in the pharmacy
Accrual period: 1986 to 1989


ParticipantsEligibility criteria: all patients admitted to the mixed ICU if their condition suggested a prolonged stay (> three days), age > 18 yrs
Exclusion criteria: age < 18 yrs, pregnancy, allergy to one of the component of the regimen, infections, antibiotic therapy 24 hrs 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 three days: treatment = 75% CTR = 80%
Stress ulcer prophylaxis applied: H2-blockers (80%)


InterventionsGroup A, CTR:
- No prophylaxis

Group B, Treatment:
- gentamycin 80 mg, polymyxin B 100 mg, nystatin 2,000,000 units, applied enterally and as a 2% paste to the oropharynx four times a day during the ICU stay
- cefotaxime 1 g/8 hrs iv for the first three 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 tracheobronchitis was based on:
the presence of increased purulent endotracheal secretions requiring frequent suctioning and the presence of a potential pathogen

Mortality: in hospital


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

de Jonge 2003

MethodsRandomised study
Blinding: Open
Randomisation method:computer-generated random-number codes kept in sealed envelopes


ParticipantsEligibility criteria: adult patients admitted to ICU: with an expected stay of at least 72 hours and an expected duration of mechanical ventilation of at least 48 hours
Exclusion criteria:
previous admission in ICU within three months iper sensitivity to study medication, pregnancy and perceived imminent death

Number of patients enrolled in the study: 934

Percentage of ventilated patients: 85%

Length of stay in ICU: median SDD group = 6.8 days
control group = 8.5 days

Type of admission diagnosis:
medical: 41%
surgical urgent: 25%
surgical elective: 34%

Severity score at admission:
APACHE II mean = 18.7
SAPS II in SDD group mean = 17.9
SAPSII in control group mean = 17.1

Percentage of immunocompromised patients
SDD group = 2.4%
control group = 1.7%

Information on prescribed antibiotics per 1,000 patients available in the main publication

No stress ulcer prophylaxis by protocol


InterventionsSDD group: topical plus systemic treatment
Topical: oral paste containing 2% polymyxin E, 2% tobramycin, 2% amphotericin
500 mg amphotericin B through gastric tubes
Systemic: cefotaxime 1000 mg four times daily for four days

Control group:
No antibiotic prophylaxis; antibiotic treatment based on clinical needs


OutcomesColonisation, antibiotic resistance
Mortality: in ICU and hospital


NotesPatients were allocated to either an SDD or a control unit to prevent cross-colonisation between SDD and ICU control patients. Standard care was the same in the two units


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Ferrer 1994

MethodsRandomised, placebo-controlled study
Blinding: double blind
Randomisation method: computer generated table
Accrual period: Jan 91 to Mar 92


ParticipantsEligibility criteria: all mechanically ventilated patients expected to remain intubated for more than three 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 three days: not available
treatment = 73% CTR = 74%
Stress ulcer prophylaxis applied: sucralfate except in patients with paralytic ileus or with upper gastrointestinal bleeding, who were treated with ranitidine


InterventionsGroup A, Treatment:
- polymyxin E 100 mg, tobramycin 80 mg, amphotericin B 500 mg applied enterally and, as a 2% paste, to the oropharynx four times a day until extubation or death
- cefotaxime 2 g/day iv for the first four days or others if required

Group B, CTR:
- Placebo
- cefotaxime 2 g/day iv for the first four days or others if required*

*patients infected on admission received adequate antibiotic treatment instead of cefotaxime


OutcomesRespiratory infections (pneumonia acquired after four 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 >= 12 x 109 WBC/l or leukopenia <= 4 x 109

Mortality: in ICU


NotesPersonal contact with the main investigator provided data about 21 patients who were excluded from the published paper (14 early extubations, six early deaths, one transfer); these data are considered in the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Finch 1991

MethodsRandomised study
Blinding: Open
Randomisation method: sealed envelopes. Randomisation series made available to the hospital Pharmacy only
Accrual period: Aug 87 to 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 three days: treatment = 58% CTR = 68%
Stress ulcer prophylaxis applied: not available


InterventionsGroup A, Treatment:
- polymyxin B 100 mg, gentamycin 120 mg, amphotericin B 500 mg applied enterally and, as a 2% paste, to the oropharynx four times a day
- cefotaxime 1 g x 3 iv for the first four 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 > 105 CFU, diagnosis of septicaemia, 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 five patients who were excluded from the published paper (one early extubation, two early deaths, one transferring, one unknown); these data are considered in the analysis. Data about respiratory infections in patients excluded from published paper are not available


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Gastinne 1992

MethodsRandomised, placebo-controlled, multicenter (15 ICUs) study Intention to treat
Blinding: double blind
Randomisation method: a randomised list of consecutive treatment assignments, performed separately in each unit.
Accrual period: Feb 90 to 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 enteropathy, pregnancy, participation in another ongoing clinical trial, refusal of consent, patients 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: 12 days
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 three days: treatment = 89% CTR = 84%
Stress ulcer prophylaxis applied: sucralfate (43% patients), H2-blockers (13% patients)


InterventionsGroup A, CTR:
- Placebo

Group B, Treatment:
- tobramycin 80 mg, polymyxin E 100 mg, amphotericin B 100 mg applied enterally and, as a 2% paste, to the oropharynx four 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


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Gaussorgues 1991

MethodsRandomised study. Intention to treat
Blinding: Open
Randomisation method: odd-even numbers
Accrual period: Sept 88 to Sept 89


ParticipantsEligibility criteria: all patients admitted to the ICU, who required mechanical ventilation and inotropic drugs for haemodynamic 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 three days: treatment = 100% CTR = 100%
Stress ulcer prophylaxis applied: sucralfate 4 g to all patients


InterventionsGroup A, Treatment:
- polymyxin E 36 mg, gentamycin 80 mg, Vancomycin 50 mg, amphotericin B 500 mg applied enterally four times a day until extubation
- amphotericin B, Clorexidine applied orally four times a day
- systemic antibiotic therapy

Group B, CTR:
- amphotericin B, Clorexidine applied orally four times a day
- systemic antibiotic therapy


OutcomesRespiratory infections: not possible to evaluate

Mortality: in ICU


NotesAll patients were infected on admission
Data about respiratory infections are not provided


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)High riskC - Inadequate

Georges 1994

MethodsRandomised, placebo-controlled study
Blinding: open
Randomisation method: sealed envelopes
Accrual period: Jun 1990 to April 1992


ParticipantsEligibility criteria: Polytrauma, expected mechanical ventilation for at least four days, age > 18 years
Exclusion criteria: Hypersensitivity to the used agents, protocol violation, obesity, ventilation < four days, patients on mechanical ventilation two days before admission, severe maxillo-facial lesions

Patients enrolled in the study: 138, but only 64 patients were analysed
Length of stay in ICU, mean: 33 days
Percentage of ventilated patients: 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 four 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


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Hammond 1992

MethodsRandomised, placebo-controlled study
Blinding: double blind
Randomisation method: computer generated random numbers.
Accrual period: Jan 89 to Dec 90


ParticipantsEligibility criteria: expected intubation for longer than 48 hrs and stay in ICU for at least five 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 three days: treatment = 54% CTR = 58%
Stress ulcer prophylaxis applied: none, H2-blockers only to high risk patients


InterventionsGroup A, Treatment:
- polymyxin E 100 mg, tobramycin 80 mg, amphotericin B 500 mg applied enterally and, as a 2% gel, to the oropharynx four times a day until 48 hrs after extubation
- cefotaxime 1 g x 3 iv for the first three days to patients untreated on admission

Group B, CTR:
- Placebo
- cefotaxime 1 g x 3 iv for the first three 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 > 1010/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, three protocol violation, one unknown); these data are considered in the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Jacobs 1992

MethodsRandomised study
Blinding: open
Randomisation method: sealed envelopes.
Accrual period: Jul 89 to Aug 90


ParticipantsEligibility criteria: expected stay in ICU > three 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 three 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 4 g to all patients not on enteral feeding


InterventionsGroup A, Treatment:
- polymyxin E 100 mg, tobramycin 80 mg, amphotericin B 500 mg applied orally and enterally four times a day until extubation
- cefotaxime 50 mg/kg/day iv x four days

Group B, CTR:
- No prophylaxis


OutcomesRespiratory infections (acquired pneumonia)
Diagnosis of infection was based on:
alveolar infiltrates on two or more chest X-rays, moderate or copious purulent tracheal aspirate, rectal temperature > 38.4°C, leucocytosis > 13 x 109/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, one HIV+); these data are considered in the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Kerver 1988

MethodsRandomised study
Blinding: open
Randomisation method: odd/even numbers
Accrual period: Jan 85 to May 86


ParticipantsEligibility criteria: all patients admitted to the surgical ICU who required care > five 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 three days: about 85%
Stress ulcer prophylaxis applied: not available


InterventionsGroup A, Treatment:
- polymyxin E 200 mg, tobramycin 80 mg, amphotericin B 500 mg applied orally and enterally four times a day
- Oral disinfectant
- cefotaxime 50 to 70 mg/kg/day iv x five to seven 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 > 10 x 103 or < 4 x 103/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 > 30 mmHg, progressive respiratory failure

Mortality


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)High riskC - Inadequate

Korinek 1993

MethodsRandomised, placebo-controlled, dual-centre study
Blinding: double blind
Randomisation method: randomisation performed by the hospital pharmacist on each unit separately
Accrual period: Mar 89 to Sep 90


ParticipantsEligibility criteria: all comatosed patients with emergency admission to two neurosurgical ICUs and intubated within 24 hrs for at least five days, age > 16 yrs
Exclusion criteria: age < 16 yrs, known immunosuppression, antibiotic treatment during the two weeks preceding ICU admission, serious injury of oropharyngeal mucosa or epistaxis, abnormal chest X-ray on admission, extubation or infection occurring within the first five 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 three 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 100 mg, tobramycin 80 mg, amphotericin B 500 mg applied enterally and, as a 2% paste, to the oropharynx four times a day for 15 days
- Vancomicin x os

Group B, CTR:
- Placebo

The non-absorbable 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 five 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 > 103 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


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Krueger 2002

MethodsRandomised, double blind, placebo-controlled, double centre study
Randomisation method: computer-generated randomisation
Accrual period: Apr 89 to Mar 91


ParticipantsEligibility criteria: expected stay in ICU > two days and at least one risk factor for infection
Exclusion criteria: patients expected to die within 48 hrs or randomisation was not achieved within 12 hrs after admission to ICU.
Patients enrolled in the study: 546, 19 patients were excluded leaving 527 patients for analysis
Percentage of ventilated patients: not available
ICU length of stay: 10 days for both groups
Type of admission diagnosis: surgical
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 three days: not available
Stress ulcer prophylaxis applied: sucralfate to all patients


InterventionsGroup A, Treatment:
- polymyxin B 50 mg, gentamycin 80 mg, applied nasally, orally and enterally four times a day during the ICU stay
- ciprofloxacin 400 mg x 2 iv x four days to uninfected patients

Group B, CTR:
- Placebo applied nasally, orally and enterally
- Placebo iv to uninfected patients


OutcomesRespiratory infections (acquired pneumonia)

Mortality in ICU


NotesInformation about accrual period and severity score was reported on an abstract previously published


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Laggner 1994

MethodsRandomised, placebo-controlled study
Blinding: double blind
Randomisation method: computer generated randomisation in time blocks. Open
Accrual period: Aug 87 to Nov 90


ParticipantsEligibility criteria: expected ventilation for five 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 five days, patients on enteral nutrition or with known allergy to sucralfate or gentamicin

Number of patients enrolled in the study: 88, but only 67 patients 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 three days: 100%
Stress ulcer prophylaxis applied: sucralfate


InterventionsGroup A, Treatment:
- gentamycin 40 mg, amphotericin B 100 mg applied to the oropharynx four times a day until extubation
- Oropharyngeal disinfectant
- aminopenicillin and clavulanic acid or other appropriate regimens

Group B, CTR:
- Placebo
- Amphotericin B 100 mg
- 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, three early enteral nutrition) are not available


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Lingnau 1997

MethodsRandomised, placebo-controlled study with three arms (one control arm and two treatment arms). Intention to treat
Blinding: double blind
Randomisation method: continuous random numbers assigned to blinded study drugs or vehicle by Biometric department.
Accrual period: Aug 89 to Jan 94


ParticipantsEligibility criteria: non infected trauma patients, age > 18 yrs, expected ventilation for at least two days, expected ICU stay for at least three 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 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 three days: treatment 1 = 2% treatment 2 = 2% CTR = 6%
Stress ulcer prophylaxis applied: free


InterventionsGroup A, Treatment 1:
- polymyxin E 100 mg, tobramycin 80 mg, amphotericin B 500 mg applied orally and enterally four times a day during the ICU stay
- ciprofloxacin 200 mg x 2 iv, for four days

Group C, CTR:
- Placebo
- ciprofloxacin 200 mg x 2 iv, for four days


OutcomesRespiratory infections (acquired pneumonia):
Diagnosis of infection was based on:
concomitant occurrence of purulent sputum, positive cultures of bronchial secretions and deterioration of lung function

Mortality: in ICU


NotesThis three arm study has been split in two comparisons; the control group C has been used twice:
comparison Lingnau a (group A versus group C)
comparison Lingnau b (group B versus group C)


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Lingnau 1997b

Methodssee Lingnau 1997


Participantssee Lingnau 1997
Only two groups of patients, group B and C, are considered in this comparison, totaling 267 patients


InterventionsGroup B, Treatment 2:
- polymyxin E 100 mg, ciprofloxacin 50 mg, amphotericin B 500 mg applied orally and enterally four times a day during the ICU stay
- ciprofloxacin 200 mg x 2 iv, for four days

Group C, CTR:
- Placebo
- ciprofloxacin 200 mg x 2 iv, for four days


Outcomessee Lingnau 1997


Notessee Lingnau 1997


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskD - Not used

Palomar 1997

MethodsRandomised, multicentric (10 ICUs) study with three arms (one treatment arm and two control arms; one control arm was excluded from meta-analysis because it was the only one receiving sucralfate)
Blinding: open
Randomisation method: sealed envelopes.
Accrual period: Jul 89 to Aug 91


ParticipantsEligibility criteria: patients requiring mechanical ventilation for more than four 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 three days: treatment = 0% CTR = 6%
Stress ulcer prophylaxis applied: sucralfate to one control group (excluded from meta-analysis), antiacids or H2-blockers to the two other groups


InterventionsGroup A, CTR 1:
- No prophylaxis

Group B, Treatment:
- polymyxin E + B 100 mg, tobramycin 80 mg, amphotericin B 500 mg applied enterally and, as a 2% paste, to the oropharynx four times a day until extubation
- cefotaxime 1 g x 3 iv for the first four days

Group C*, CTR 2:
- cefotaxime 1 g x 3 iv for the first four 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 tracheobronchitis 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 the published paper (seven early extubations, five early deaths, three protocol violation, one other); these data are considered in the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Pneumatikos 2002

MethodsRandomised, placebo-controlled
Blinding: outcome assessor
Randomisation method: not stated


ParticipantsElegibility criteria: patients with multiple trauma admitted to the intensive care unit who required intubation and had an expected time for mechanical ventilation exceeding five days
Absence of cardiopulmonary disease, negative chest radiography, and a PaO2/FIO2 ratio higher than 300 mmHg

Patients enrolled in the study: 61

Percentage of ventilated patients: 100%
ICU length of stay, median:
Treatment = 16 days
Control = 23 days
Type of admission diagnosis:
trauma = 100%

Severity score on admission: APACHE II
treatment = 18.1
control = 19.1
Percentage of immunocompromised patients: not stated
Percentage of patients treated with systemic antibiotic therapy:
not stated
Stress ulcer prophylaxis applied: H2 blockers or sucralfate
Treatment = 26%
Control = 19%


InterventionsGroup A, treatment:
polymyxin 73 mg,
tobramycin 73 mg, amphotericin 500 ml in 500 ml 0.9 saline solution at an infusion rate of 2 ml/hr in the subglottic area for the entire period of the study

Group B CTR:
placebo


OutcomesVentilator associated pneumonia (VAP) defined as presence of new and persistent pulmonary infiltrates in addition to two of the following criteria: body temperature > 38.3 °C, leukocytes/mm3) or leukopenia (< 4000 leukocytes/mm3) and purulent tracheal secretions. The diagnosis of VAP was confirmed by quantitative cultures.

Mortality: not specified


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Pugin 1991

MethodsRandomised, placebo-controlled study
Blinding: double blind
Randomisation method: sealed envelopes
Accrual period: Apr 89 to 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 three days: treatment = 46% CTR = 53%
Stress ulcer prophylaxis applied: sucralfate (61%), ranitidine (11%)


InterventionsGroup A, Treatment:
- polymyxin B sulfate 150 mg, neomycin sulfate 1 g, vancomycin hydrochloride 1 g applied as a solution to the retropharynx six 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 seven during the course of intubation and that remained elevated (=7) for at least three 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 the published paper (20 early extubations, seven early deaths); these data are considered in the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Quinio 1995

MethodsRandomised, placebo-controlled study. Intention to treat
Blinding: double blind
Randomisation method: randomisation made by the Pharmacy's Service according to computer generated random numbers.
Accrual period: Jan 91 to Jan 93


ParticipantsEligibility criteria: trauma patients intubated within 24 hrs and ventilated for more than 48 hrs, ICU stay > five days and decontamination for more than four 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 three 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 80 mg, amphotericin B 500 mg applied enterally and in the nares and, as a 2% paste, to the oropharynx four 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


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Rocha 1992

MethodsRandomised, placebo-controlled study
Blinding: double blind
Randomisation method: made by the Pharmacy's service according to computer generated random numbers
Accrual period: Sept 89 to Oct 90


ParticipantsEligibility criteria: expected mechanical ventilation for more than three days, stay in ICU more than five days
Exclusion criteria: infection or strong suspicion of this at the start of ventilation, antibiotic treatment in the previous seven 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 eight 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 = nine
Percentage of immunocompromised patients: 0.7%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first three days: treatment = 0% CTR = 0%
Stress ulcer prophylaxis applied: H2-blockers and antiacids


InterventionsGroup A, Treatment:
- polymyxin E 100 mg, tobramycin 80 mg, amphotericin B 500 mg applied enterally and, as a 2% paste, to the oropharynx four times a day
- cefotaxime 6 g/day iv for the first four 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 extubations, 31 early deaths, two protocol violation, two other); these data are considered in the analysis. Data about respiratory infections in excluded patients are not available


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Rodriguez-Rolda 1990

MethodsRandomised, placebo-controlled, dual-center study
Blinding: double blind
Randomisation method: odd and even numbers
Accrual period: Jun 88 to 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 three 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 four 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 bronchorrhoea, 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 > 103 CFU/ml (in six 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 three patients who were excluded from the published paper (two early deaths, one other); these data are considered in the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)High riskC - Inadequate

Sanchez-Garcia 1992

MethodsRandomised, placebo-controlled, multicentric (five ICUs) study
Blinding: double blind
Randomisation method: sealed envelopes.
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 three 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 100 mg, gentamycin 80 mg, amphotericin B 500 mg applied orally and enterally four times a day until extubation
- Ceftriaxone 2 g/day iv x three 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 three 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 extubations, 12 early deaths, 17 protocol violation, two transferring, two other); these data are considered in the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Stoutenbeek 1996

MethodsRandomised, placebo-controlled study
Blinding: double blind.
Randomisation method: closed envelope method (the code was known by the pharmacist only).
Accrual period: Nov 84 to 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 five days or discharged from ICU within seven 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 three 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 100 mg, tobramycin 80 mg, amphotericin 500 mg applied enterally and, as a 2% paste, to the oropharynx four times a day until ICU discharge
- cefotaxime 50 to 100 mg/kg/day iv for the first five days

Group B, CTR:
- Placebo
- cefotaxime 50 to 100 mg/kg/day iv for the first five 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 > 12.5 x 109/l or leukopenia < 4 x 10^9/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 extubations, four early deaths, three other) are considered in the analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Stoutenbeek 2007

MethodsRandomised, multicenter study. Intention to treat
Blinding: open
Randomisation method: randomisation lists prepared by the Biometrical Department and supplied with sealed envelopes
Accrual period: Oct 91 to Jun 94


ParticipantsEligibility criteria: patients admitted within 24 hrs after nonpenetrating blunt trauma with an HTI-ISS >= 16, necessitating mechanical ventilation, age > 18 yrs
Exclusion criteria: previous antibiotic use for more than three 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 401 patients were analysed
Percentage of ventilated patients: 100%
Median length of ICU stay: SDD = 13 days, CTR = 12 days
Median duration of mechanical ventilation: SDD = nine days, CTR = eight days
Type of admission diagnosis: trauma 100%
Severity score on admission - APACHE II median: SDD = 15, CTR = 14 and HTI-ISS median: SDD = 34, CTR = 29
Percentage of immunocompromised patients: 0%
Percentage of patients treated with systemic antibiotic therapy (not stated in the protocol) in the first three days: treatment = 46% CTR = 88%
Stress ulcer prophylaxis applied: sucralfate, H2-blockers, omeprazole; no sucralfate


InterventionsGroup A, Treatment:
- polymyxin E, tobramycin, amphotericin B administered through the nasogastric tube and applied to the buccal mucosa four times a day until discharge
- cefotaxime 1 g every six hours for four days

Group B, CTR:
- Standard antibiotic prophylaxis used in each centres (no fluoroquinolones)


OutcomesPrimary: Mortality from infection or multiple organ failure in ICU or up to two weeks after discharge

Secondary: incidence of infection, multiple organ failure and antibiotic usage

The maximum observation period was three months
Patients dying within 24 hours after injury or dying from craniocerebral trauma were excluded

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 tracheal aspirate, fever > 38.5°C, leukocytosis > 12,000/ml or leukopenia < 4000/ml
Diagnosis of tracheobronchitis was based on the same criteria except for the radiographic changes
Mortality: in ICU or up to two weeks after discharge


Notesfour patients were excluded from the final analysis after randomisation: two because they did not fulfil the inclusion criteria, the data for one patient were not available and one was lost to follow-up after the 7th day


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Ulrich 1989

MethodsRandomised, placebo-controlled study
Blinding: open
Randomisation method: sealed envelopes containing a random code for clusters of four patients
Accrual period: Oct 86 to Sep 87


ParticipantsEligibility criteria: patients expected to stay in the ICU more than five days and ventilated more than 48 hrs
Exclusion criteria: patients 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 three days: treatment = 83% CTR = 81%
Stress ulcer prophylaxis applied: not available


InterventionsGroup A,Treatment:
- polymyxin E 100 mg, norfloxacin 50 mg, amphotericin B 500 mg, applied enterally and, as a 2% paste, to the oropharynx four times a day
- Trimethoprim 500 mg 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


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Unertl 1987

MethodsRandomised study
Blinding: outcome assessor
Randomisation method: blocked randomisation scheme and the sealed envelope technique. Blind
Accrual period: May 84 to 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 > six 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 three days: not available
Stress ulcer prophylaxis applied: H2-blockers to all patients and antiacids if pH < 4


InterventionsGroup A, Treatment:
- polymyxin B 50 mg, gentamycin 80 mg, applied orally, nasally and enterally four times a day until extubation
- Amphoterycin B 300 mg applied orally four 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 > 3 x 104 granulocytes/mcl and at least two 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 maintain oxygen tension.
'Definite' is an infiltrate confirmed by two blind independent radiologists and not reversible after chest physiotherapy

Mortality: in ICU


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Verwaest 1997

MethodsRandomised study with three arms (one control arm and two treatment arms)
Blinding: open
Randomisation method: sealed envelopes with computer generated random numbers
Accrual period: Sept 89 to 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 patients, A and B, are considered in this comparison, totaling 440 patients)
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 three days: treatment one = 34% treatment twp = 31% CTR = 34%
Stress ulcer prophylaxis applied: sucralfate 2 g x 4


InterventionsGroup A, CTR:
- No prophylaxis, antibiotic therapy was used only if an infection was suspected

Group B, Treatment 1:
- Ofloxacin 200 mg x 2, Amphoterycin B 500 mg x 4 applied enterally and, as a 2% paste, to the oropharynx four times a day until discharge
- Ofloxacin 200 mg iv x four 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


NotesPersonal contact with the main investigator provided mortality data about 82 patients who were excluded (33 early deaths, 49 other); these data are considered in the analysis.Data about respiratory infections in excluded patients are not available


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

Wiener 1995

MethodsRandomised, placebo-controlled study
Blinding: double blind
Randomisation method: random number table in blocks of six patients
Accrual period: eight months


ParticipantsEligibility criteria: expected intubation for more than 48 hrs, inclusion within 18 hrs of intubation, age > 18 yrs
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 patients were excluded leaving 61 patients 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 three days: treatment = 93% CTR = 81%
Stress ulcer prophylaxis applied: H2-blockers to most patients


InterventionsGroup A, Treatment:
- polymyxin E 100 mg, gentamycin 80 mg, nystatin 2,000,000 UI applied enterally four 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 > 103 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


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskB - Unclear

Winter 1992

MethodsRandomised study
Blinding: open.
Randomisation method: sealed envelopes based on a computer generated table of random numbers.
Accrual period: Jul 88 to May 90


ParticipantsEligibility criteria: patients likely to remain in the ICU for at least 48 hrs
Exclusion criteria: allergy to the antibiotics used, age > 85 yrs, pregnancy

Patients enrolled in the study: 183
Percentage of ventilated patients: 92%
Length of stay in ICU, median = four 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 three 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 four times a day
- Ceftazidime 50mg/kg/day iv x three 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 > 12 x 109/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


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskA - Adequate

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Arnow 1996The study included a selected population of patients undergoing liver transplant

Barret 2001The study included only paediatric burns patients

Bion 1994The study included a selected population of patients undergoing liver transplant

Bouter 2002The study included only patients undergoing cardiopulmonary by-pass

de la Cal 2005The study included only critically ill burns patients

de Smet 2009The study adopted a cluster design with type of treatments alternated for specific periods of time across participating hospitals. As a consequence patients were not properly randomised and the study could be affected by selection bias.

Flaherty 1990The study included a selected population of cardio surgical patients

Garbino 2002The study tested the effectiveness of fluconazole as both groups received SDD

Hellinger 2002The study included only liver transplant patients

Hunefeld 1989After contacting the principal investigator it become apparent that it was not a randomised study

Jacobs 1995This study, included in the previous version of this review as a personal contact with the principal investigator, has been excluded due to lack of feedback from the trial author. To date, this study has never been published

Lenhart 1994This study, included in the previous version of this review as a congress proceeding, has been replaced by its published article (Krueger 2002)

Lipman 1994After contacting the principal investigator it become apparent that it was not a randomised study

Luiten 1995The study included a selected population of patients affected by pancreatitis characterised by a low percentage of ICU admissions.

Martinez 1994The study compared the effect of two different prophylactic regimens without a control group

Martinez-Pellus 1993The study included a selected population of cardio surgical patients

Nardi 2001The study tested the effectiveness of mupirocin as both groups received SDD

Rayes 2002The study included only liver transplant patients

Rolando 1996The study included a selected population of patients with acute hepatic failure

Ruza 1998The study included only paediatric burns patients

Schardey 1997The study included a selected population of patients undergoing gastric surgery and characterised by a low percentage of ICU admission

Smith 1993The study included only paediatric, liver transplant patients

Stoutenbeek 2This unpublished study, included in the previous version of this review, has been replaced by its published article (Stoutenbeek 2007)

Tetteroo 1990The study included a selected population of patients undergoing oesophageal resection and characterised by a short length of stay in ICU

Zobel 1991The study included only paediatric patients

Zwaveling 2002The study included only liver transplant patients

 
Comparison 1. Topical plus systemic versus no prophylaxis

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall mortality174075Odds Ratio (M-H, Fixed, 95% CI)0.75 [0.65, 0.87]

 2 Mortality according to quality of allocation concealment174075Odds Ratio (M-H, Fixed, 95% CI)0.75 [0.65, 0.87]

    2.1 Adequate
103336Odds Ratio (M-H, Fixed, 95% CI)0.77 [0.66, 0.90]

    2.2 Not adequate
7739Odds Ratio (M-H, Fixed, 95% CI)0.67 [0.48, 0.93]

 3 Mortality according to blinding of the studies174075Odds Ratio (M-H, Fixed, 95% CI)0.75 [0.65, 0.87]

    3.1 Double-blind
41013Odds Ratio (M-H, Fixed, 95% CI)0.63 [0.48, 0.83]

    3.2 Open
133062Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.68, 0.95]

 4 RTIs163024Odds Ratio (M-H, Random, 95% CI)0.28 [0.20, 0.38]

 5 RTIs according to quality of allocation concealment163024Odds Ratio (M-H, Random, 95% CI)0.28 [0.20, 0.38]

    5.1 Adequate
92335Odds Ratio (M-H, Random, 95% CI)0.36 [0.27, 0.47]

    5.2 Not adequate
7689Odds Ratio (M-H, Random, 95% CI)0.19 [0.10, 0.37]

 6 RTIs according to blinding of the studies163024Odds Ratio (M-H, Random, 95% CI)0.28 [0.20, 0.38]

    6.1 Double-blind
4963Odds Ratio (M-H, Random, 95% CI)0.40 [0.30, 0.53]

    6.2 Open
122061Odds Ratio (M-H, Random, 95% CI)0.22 [0.14, 0.34]

 
Comparison 2. Topical versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall mortality203016Odds Ratio (M-H, Fixed, 95% CI)0.97 [0.82, 1.16]

    1.1 Topical plus systemic versus systemic
71233Odds Ratio (M-H, Fixed, 95% CI)0.98 [0.73, 1.32]

    1.2 Topical versus no prophylaxis
131783Odds Ratio (M-H, Fixed, 95% CI)0.97 [0.79, 1.20]

 2 Mortality according to quality of allocation concealment203016Odds Ratio (M-H, Fixed, 95% CI)0.97 [0.82, 1.16]

    2.1 Adequate
2139Odds Ratio (M-H, Fixed, 95% CI)0.64 [0.27, 1.52]

    2.2 Not adequate
182877Odds Ratio (M-H, Fixed, 95% CI)0.99 [0.83, 1.18]

 3 Mortality according to blinding of the studies203016Odds Ratio (M-H, Fixed, 95% CI)0.98 [0.82, 1.16]

    3.1 Double-blind
152601Odds Ratio (M-H, Fixed, 95% CI)0.99 [0.83, 1.20]

    3.2 Open
5415Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.56, 1.37]

 4 RTIs182850Odds Ratio (M-H, Random, 95% CI)0.44 [0.31, 0.63]

    4.1 Topical plus systemic versus systemic
61115Odds Ratio (M-H, Random, 95% CI)0.79 [0.56, 1.13]

    4.2 Topical versus no prophylaxis
121735Odds Ratio (M-H, Random, 95% CI)0.34 [0.21, 0.55]

 5 RTIs according to quality of allocation concealment182850Odds Ratio (M-H, Random, 95% CI)0.44 [0.31, 0.63]

    5.1 Adequate
191Odds Ratio (M-H, Random, 95% CI)0.18 [0.04, 0.91]

    5.2 Not adequate
172759Odds Ratio (M-H, Random, 95% CI)0.46 [0.32, 0.66]

 6 RTIs according to blinding of the studies182850Odds Ratio (M-H, Random, 95% CI)0.44 [0.31, 0.63]

    6.1 Double-blind
142553Odds Ratio (M-H, Random, 95% CI)0.52 [0.36, 0.75]

    6.2 Open
4297Odds Ratio (M-H, Random, 95% CI)0.20 [0.10, 0.41]