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The endogenous (solid arrows) and exogenous (gray arrows) routes of colonization and infection of lower airways. In patients who are endotracheally ventilated, the endogenous pathway prevails, as opposed to the exogenous route being substantial once the patient receives a tracheotomy.

The endogenous (solid arrows) and exogenous (gray arrows) routes of colonization and infection of lower airways. In patients who are endotracheally ventilated, the endogenous pathway prevails, as opposed to the exogenous route being substantial once the patient receives a tracheotomy.

Table 1. 
Patient Demographics
Patient Demographics
Table 2. 
Ventilation Periods for the 2 Forms of Ventilation
Ventilation Periods for the 2 Forms of Ventilation
Table 3. 
Impact of Mode of Ventilation on the Number of Colonized/Infected Children and on the Number of Episodes of Colonization and Infection*
Impact of Mode of Ventilation on the Number of Colonized/Infected Children and on the Number of Episodes of Colonization and Infection*
Table 4. 
Impact of Mode of Ventilation on the 3 Pathways Causing Lower Airway Colonization/Infection*
Impact of Mode of Ventilation on the 3 Pathways Causing Lower Airway Colonization/Infection*
Table 5. 
Microorganisms Causing Colonization/Infection*
Microorganisms Causing Colonization/Infection*
1.
Bartlett  JGFaling  LJWilley  S Quantitative tracheal bacteriologic and cytologic studies in patients with long-term tracheostomies. Chest.1978;74:635-639.
2.
Niederman  MSFerranti  RDZiegler  AMerrill  WWReynolds  HY Respiratory infection complicating long-term tracheotomy: the implication of persistent gram-negative tracheobronchial colonization. Chest.1984;85:39-44.
3.
Palmer  LBDonelan  SVFox  GBellemore  EGreene  WH Gastric flora in chronically mechanically ventilated patients: relationship to upper and lower airway colonization. Am J Respir Crit Care Med.1995;151:1063-1067.
4.
Niederman  MSMantovani  RSchoch  PPapas  JFein  AM Patterns and routes of tracheobronchial colonization in mechanically ventilated patients: the role of nutritional status in colonization of the lower airway by Pseudomonas species. Chest.1989;95:155-161.
5.
Rogers  JH Tracheostomy and decannulation.  In: Kerr  AG, ed. Scott-Brown's Otolaryngology.Vol 6.6th ed. London, England: Butterworths; 1997:471-486.
6.
Tym  GM Home tracheostomy care.  In: Kerr  AG, ed. Scott-Brown's Otolaryngology.Vol 6.6th ed. London, England: Butterworths; 1997:487-494.
7.
Torres  AMartos  ADe La Bellacasa  JP  et al Specificity of endotracheal aspiration, protected specimen brush, and bronchoalveolar lavage in mechanically ventilated patients. Am Rev Respir Dis.1993;147:952-957.
8.
Marquette  CHGeorges  HWallet  F  et al Diagnostic efficiency of endotracheal aspirates with quantitative bacterial cultures in intubated patients with suspected pneumonia: comparison with the protected specimen brush. Am Rev Respir Dis.1993;148:138-144.
9.
van Saene  HKFDamjanovic  VMurray  AEde la Cal  MA How to classify infections in intensive care units: the carrier state, a criterion whose time has come? J Hosp Infect.1996;33:1-12.
10.
Lepper  MHKofman  SBlatt  N  et al Effect of eight antibiotics used singly and in combination on the tracheal flora following tracheotomy in poliomyelitis. Antibiot Chemother.1954;4:829-843.
11.
Palmer  LBSmaldone  GCSimon  SRO'Riordan  TGCuccia  A Aerosolized antibiotics in mechanically ventilated patients: delivery and response. Crit Care Med.1998;26:31-39.
12.
Klastersky  JHuysmans  EWeerts  DHensgens  CDaneau  D Endotracheally administered gentamicin for the prevention of infections of the respiratory tract in patients with tracheostomy: a double-blind study. Chest.1974;65:650-654.
13.
Klastersky  JHensgens  CNoterman  JMouawad  EMeunier-Carpentier  F Endotracheal antibiotics for the prevention of tracheobronchial infections in tracheotomized unconscious patients: a comparative study of gentamicin and aminosidin–polymyxin B combination. Chest.1975;68:302-306.
14.
Silvestri  LMannucci  Fvan Saene  HK Selective decontamination of the digestive tract: a life saver. J Hosp Infect.2000;45:185-190.
15.
Morar  PMakura  ZJones  A  et al Topical antibiotics on tracheostoma prevents exogenous colonization and infection of lower airways in children. Chest.2000;117:513-518.
Original Article
September 2002

Differing Pathways of Lower Airway Colonization and Infection According to Mode of Ventilation (Endotracheal vs Tracheotomy)

Author Affiliations

From the Departments of Otorhinolaryngology (Drs Morar, Singh, Makura, and Jones), Paediatric Intensive Care (Drs Baines, Selby, and Sarginson), and Clinical Microbiology and Infection Control (Ms Hughes and Dr van Saene), Royal Liverpool Children's NHS Trust of Alder Hey, Liverpool, England.

Arch Otolaryngol Head Neck Surg. 2002;128(9):1061-1066. doi:10.1001/archotol.128.9.1061
Abstract

Objectives  To determine whether the pathogenesis of lower airway colonization and infection was endogenous (via the oropharynx) or exogenous (via the endotracheal tube or tracheotomy) during the 2 modes of ventilation in the same subset of children requiring long-term ventilation.

Design  Prospective, observational cohort study.

Setting  A pediatric intensive care unit and a respiratory ward.

Patients  Consecutive admissions between September 1, 1993, and August 30, 1998.

Measurements and Main Results  Cultures were obtained simultaneously from the oropharynx and tracheobronchial tree on admission to the pediatric intensive care unit, at placement of the tracheotomy, and afterward twice weekly. Forty-five patients were studied. Lower airways were always sterile in 6 children, 39 children (87%) developed a total of 82 episodes of colonization, and 17 (38%) progressed to 25 episodes of infection. The number of infected children was halved once they had a tracheotomy (7 children [16%]). Of the 107 episodes of colonization and infection, 41 and 66 occurred during endotracheal ventilation and via a tracheotomy, respectively. Primary endogenous episodes of colonization and infection due to bacteria present in the admission flora in the pediatric intensive care unit were significantly more common with endotracheal ventilation than during ventilation via a tracheotomy (31/41 [76%] vs 36/66 [55%]; P = .03). Secondary endogenous and exogenous episodes of colonization and infection due to bacteria associated with the respiratory ward were significantly more frequent when ventilation was continued through a tracheotomy than during endotracheal ventilation (30/66 [45%] vs 10/41 [24%]; P = .02).

Conclusions  Surveillance samples allow the distinction between primary endogenous ("imported" bacteria) from secondary endogenous and exogenous ("nosocomial" microorganisms) colonization and infection. This classification permits the development of preventive strategies to control both endogenous and exogenous pathways.

THE OROPHARYNGEAL flora has been compared with the flora of the lower airways in adult patients requiring ventilation endotracheally and subsequently via a tracheotomy.14 Longitudinal serial samples from the oropharynx and lower airways are required for that comparison. The 3 studies in adult patients with tracheotomies13 showed that the microorganisms isolated from the lower airways differed from the bacteria carried in the oropharynx. Bartlett et al1 demonstrated in 16 patients that there was a poor correlation between oropharyngeal and tracheal cultures. Aerobic gram-negative bacilli (AGNB), mainly Pseudomonas and Serratia species, were the predominating potential pathogens. Niederman et al2 examined 14 adult patients and found that the flora differed at the 2 sites and that Pseudomonas species persisted more often in the tracheal than in the oropharyngeal cultures. Palmer et al3 confirmed in 7 patients that colonization differed between the oropharynx and trachea. Pseudomonas and Serratia species again emerged as the common potential pathogens. In 14 endotracheally ventilated patients, Niederman et al4 reported that Pseudomonas species were found more often in the tracheobronchial tree than in the oropharynx.

As pediatric studies using the design of obtaining cultures simultaneously from the oropharynx and tracheobronchial tree were lacking, our group embarked on a prospective observational cohort study in 45 children requiring long-term ventilation initially via an endotracheal tube and subsequently via a tracheotomy. The objective was to unravel the pathway of lower airway infections: whether the pathogenesis of colonization and infection was endogenous (via the oropharynx) or exogenous (via the endotracheal tube or tracheotomy) during the 2 different modes of ventilation (Figure 1).

PATIENTS AND METHODS

This prospective observational investigation was undertaken during a 5-year period in the pediatric intensive care unit (PICU) and afterward at the respiratory ward of the Alder Hey Children's Hospital, Liverpool, England, during the period from September 1, 1993, through August 30, 1998. Children requiring mechanical ventilation, initially endotracheally and subsequently via tracheotomy, were consecutively enrolled into this cohort study of children with tracheotomies.

PATIENTS

Forty-five patients, 33 boys and 12 girls, were enrolled consecutively during the 5 years. Median age was 6.4 months, with a range of 0 to 180 months. The mean age was 42.8 months (SD, 65 months) at the time of admission to the PICU (Table 1). Twelve of the children had underlying neurologic disease. This included 7 children with cerebral palsy, 3 patients with Guillain-Barré syndrome, and 1 patient each with status epilepticus and central apnea syndrome. Four patients underwent tracheotomies for purely pulmonary problems. Airway obstruction was the indication for tracheotomy in 26 patients. Of these, 10 were for upper airway obstructions, 8 for subglottic stenosis, 3 for bilateral vocal cord palsy, 2 for subglottic hemangiomas, and 1 each for extratracheal compression, laryngeal papilloma, and tracheomalacia. One patient had a myopathic disorder, requiring a permanent tracheotomy, and 2 patients had difficulties being weaned off the ventilator after a spinal operation for the correction of kyphoscoliosis.

TRACHEOTOMY

All tracheotomies were performed electively by means of the routine methods used in children by most authorities.5 Immediate aftercare, including daily stoma care, suctioning, and change of tracheotomy tube, were all done under strict protocols of hygiene and sterility.6

END POINTS

There was only 1 intervention: the change of mode of ventilation, initially endotracheally and subsequently via tracheotomy. The impact of the placement of a tracheotomy was evaluated by comparing the following factors for both ventilation modes: (1) the number of children who were colonized with potentially pathogenic microorganisms (PPMs) in the lower airways; (2) the number of episodes of colonization; (3) the number of children with infected lower airways; (4) the number of infection episodes; and (5) the number of episodes of primary endogenous, secondary endogenous, and exogenous colonization and infection.

SAMPLING

Surveillance samples of the oropharynx were obtained immediately on admission to the PICU before endotracheal ventilation and before the placement of the tracheotomy, and twice weekly afterward. The reason for taking these samples is to detect the carrier state of the potential pathogens that allow us to distinguish the endogenous from the exogenous pathway.

Diagnostic samples of lower airway secretions were taken once weekly, and on clinical indication, ie, tracheal aspirates that were turbid.

ANTIBIOTIC POLICY DURING THE STUDY

Systemic antibiotics were given only in case of infection. Infection was diagnosed on the basis of clinical signs of infection, including temperature greater than 38.5°C, leukocytosis with a white blood cell count greater than 12 × 103/µL, and elevated C-reactive protein level to greater than 15 µg/mL, combined with purulent tracheal aspirates yielding 106 colony-forming units (CFU)/mL or more.7,8 All requirements had to be fulfilled for the diagnosis of infection. Tracheobronchitis was distinguished from pneumonia by the absence of chest radiographic changes. Infection due to gram-positive bacteria was, in general, treated with a first-generation cephalosporin, while a third-generation cephalosporin was given in children who developed a lower airway infection caused by AGNB. Infection in general was treated with a 5-day course of antibiotics, followed by clinical reexamination of the patient.

DEFINITIONS

The following definitions were used, in accordance with van Saene et al.9

1. Carriage or the carrier state existed when the same bacterial strain was isolated from at least 2 consecutive throat samples, in any concentration, during a period of at least 1 week.

2. Colonization of the lower airways was defined as the presence of a microorganism in the lower airways; the diagnostic sample yielded less than 106 CFU/mL of diagnostic sample. The concentration of leukocytes in the lower airway secretions was, in general, few (+) or moderate (++), on a semiquantitative scale of +, ++, and +++ (many).

3. Infection of the lower airways was defined as a microbiologically proved diagnosis of systemic inflammation. The diagnostic sample obtained from the lower airways yielded greater than or equal to 106 CFU/mL of sample, and there were many leukocytes in the lower airway secretions.

Tracheobronchitis was defined as follows: (a) purulent endotracheal aspirate (white blood cells +++), (b) fever (temperature, >38.5°C), (c) leukocytosis (white blood cell count, >12 × 103/µL) or leukopenia (white blood cell count, <4 × 103/µL), (d) 106 CFU/mL or more of tracheal aspirate, and (e) elevated C-reactive protein level of greater than 15 µg/mL.

Bronchopneumonia was diagnosed by means of the same 5 criteria as above, combined with the presence of a new or progressive pulmonary infiltrate on chest radiograph for more than 48 hours.

4. Primary endogenous colonization and infection was defined as colonization and infection of the lower airways caused by a PPM isolated from the lower airway secretions, and carried by the patient in the throat, at the time of admission to the PICU and/or tracheotomy.

5. Secondary endogenous colonization and infection was defined as colonization and infection of the lower airways caused by a PPM isolated from the tracheal aspirate, and not carried in the throat at the time of admission to the PICU and/or tracheotomy, but appearing later.

6. Exogenous colonization and infection was defined as colonization and infection of the lower airways caused by a PPM isolated from the tracheal aspirate that was not previously carried by the child in the throat at any time.

7. Indigenous flora were microorganisms, eg, viridans streptococci, carried by healthy individuals at high concentrations, ie, 106 CFU/mL of saliva or more.

8. Community PPMs were PPMs carried by varying percentages of healthy people, including Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus.

9. Hospital PPMs included AGNB such as Klebsiella, Enterobacter, Acinetobacter, Pseudomonas, and Stenotrophomonas species, and methicillin-resistant S aureus. They are abnormal in healthy people and are carried by individuals with both acute and chronic underlying diseases.

10. Nosocomial microorganisms were microorganisms that were not present in the patients' admission flora to the PICU, or at the time of placement of a tracheotomy. Nosocomial microorganisms were PICU and/or respiratory ward related and caused secondary endogenous and exogenous colonization and infection of the lower airways.

STATISTICAL ANALYSIS

A statistical package (Arcus QuickStat; StatsDirect Ltd, Ashwell, England) was used for analysis of the data. The number of children colonized and infected before and after tracheotomy was analyzed by means of McNemar 2-tailed test after Liddell. Proportions analysis using a 2-tailed exact method with 95% confidence intervals was used for the comparison of the percentages of episodes of both colonization and infection, during the pretracheotomy and posttracheotomy periods. The same analysis was used to compare the different types of colonization and infection during the 2 modes of assisted ventilation: primary endogenous, secondary endogenous, and exogenous. Nosocomial colonization and infection episodes accounted for only secondary endogenous and exogenous categories.

RESULTS
PATIENTS

The 45 children had assisted ventilation for a median period of 12 days (95% confidence interval, 7-24 days; range, 0-103 days) in the pretracheotomy period, via an endotracheal tube, for a total of 916 days. Assisted mechanical ventilation continued after tracheotomy via a tracheotomy tube for a further total of 1559 days, with a median of 12 days (95% confidence interval, 2-28 days; range, 1-281 days) (Table 2).

Of the 45 children enrolled, 6 children who required long-term ventilation had sterile lower airways throughout the study period whether they were ventilated via an endotracheal route or via a tracheotomy. Of the 39 children (87%) who developed a total of 82 episodes of colonization, 17 (38%) progressed to a total of 25 episodes of infection consisting of both tracheobronchitis and pneumonia. A total of 122 PPMs were involved in the 107 episodes of colonization and infection in 39 children.

IMPACT OF PLACEMENT OF TRACHEOTOMY

Both the number of children with colonized airways and the number of episodes of colonization increased significantly after ventilation through a tracheotomy (Table 3). As the children recovered once they had received a tracheotomy, the rate of infected patients as well as the number of infection episodes decreased. However, these differences were not statistically significant. Table 4 shows the impact of the mode of ventilation on the 3 types of lower airway colonization and infection.

Primary endogenous episodes of colonization and infection of the lower airways were significantly more common when patients were endotracheally ventilated compared with tracheotomy (31/41 [76%] vs 36/66 [55%]; P = .03). In other words, microorganisms carried in the oropharynx at the time of endotracheal admission to the PICU caused three fourths of all episodes during endotracheal ventilation, while half of all episodes that developed after placement of tracheotomy were due to throat bacteria present at the time of tracheotomy.

Ward-related bacteria were responsible for 45% (30/66) of all episodes of colonization and infection once ventilation was continued through a tracheotomy on the respiratory ward. In contrast, 24% (10/41) of all episodes were due to bacteria associated with the PICU during ventilation. This difference was significant at a level of P = .02.

MICROORGANISMS INVOLVED IN COLONIZATION AND INFECTION EPISODES

A total of 81 microorganisms were isolated from the lower airway secretions of children during 67 episodes of primary endogenous colonization and infection. Community PPMs, including S pneumoniae, H influenzae, Moraxella catarrhalis, and S aureus, and AGNB (mainly Pseudomonas aeruginosa) were equally distributed among the endotracheal ventilation episodes and the episodes incurred during ventilation via a tracheotomy (Table 5). There were a total of 40 episodes of secondary endogenous and exogenous colonization and infection, yielding 42 microorganisms. There were 10 episodes of secondary endogenous and exogenous development caused by 2 community bacteria (S aureus in both) and 8 AGNB (P aeruginosa in 5) during endotracheal ventilation. After the placement of a tracheotomy, 30 episodes of secondary endogenous and exogenous pathogenesis developed and were caused by 16 "community" bacteria (S aureus in 15), 14 AGNB (P aeruginosa in 7), and 2 methicillin-resistant S aureus.

COMMENT

Changing the mode of ventilation from endotracheal to a tracheotomy resulted in most children (87%) being colonized with bacteria in their lower airways. However, the number of infected children was halved once they had a tracheotomy (16%). Half of all episodes of colonization and infection during ventilation via a tracheotomy were caused by microorganisms carried in the throat at placement of the tracheotomy; the other half were due to bacteria acquired on the respiratory ward. This contrasts with the microbial distribution during endotracheal ventilation: 25% PICU acquired and 75% of episodes due to bacteria present in the admission flora.

Apparently, keeping the lower airways sterile in a child with a tracheotomy is impossible. The wound created by the tracheotomy represents an anatomic aberration. The presence of a plastic device always causes a low grade of mucocutaneous inflammation. The pH of the lower airway secretions is increased and the normal position of the trachea is altered. A tracheotomy bypasses the physiologic filter system limiting bacterial invasion into the lower airways. In the presence of microbial exposure, microorganisms show an affinity for the tracheotomy rather than the oropharynx as the site of acquisition. In addition, introduction of microorganisms directly into the lower airways via the tracheotomy as a result of repeated suctioning and manipulation of the trachea represents an important exogenous pathway. However, only 16% of the children with a tracheotomy had an infection, mainly because of a substantial improvement of their underlying medical condition. The infection rate was 30% when they required intensive care including endotracheal ventilation.

Most children left the PICU for the respiratory ward once they had a tracheotomy. Half of all colonization and infection episodes were due to bacteria that the patients did not carry in their throats but acquired on the respiratory unit, mainly via the tracheotomy, ie, exogenous pathway. In contrast, 75% of all episodes that developed during endotracheal ventilation were caused by bacteria not related to the PICU but present in the oropharyngeal admission flora.

We believe that the criterion of the oropharyngeal carrier state allowed us to unravel the different routes of colonization and infection due to the change of mode of ventilation. The traditional time cutoff of 48 hours used in the 4 adult studies14 failed to distinguish the 3 forms of colonization and infection of the lower airways. The distinction between primary endogenous colonization and infection due to bacteria not related to the PICU and respiratory ward from secondary endogenous and exogenous colonization and infection caused by PICU and respiratory ward bacteria has proved to be helpful in unraveling the impact of the change of mode of ventilation.

Attempts to control colonization and infection of the lower airways in patients with a tracheotomy date from the epidemic of poliomyelitis in 1952.10 Lepper et al10 used aerosols of polymyxin B sulfate in 72 patients to prevent colonization and infection by P aeruginosa. While P aeruginosa was effectively controlled, the polymyxin aerosols failed in controlling S aureus and Proteus species intrinsically resistant to the polymyxins. Fifty years later, Palmer et al11 evaluated the efficacy of aerosolized aminoglycosides, gentamicin sulfate and amikacin sulfate, delivered via a nebulizer to the lower airways of 6 patients. The investigators reported the eradication of Pseudomonas species, Serratia marcescens, and Enterobacter aerogenes. In the 1970s, Klastersky et al12 instilled, intratracheally, aminoglycosides alone and in combination with polymyxin B in neurosurgical patients with tracheotomies. In the first study, 85 patients were randomized to receive either endotracheal gentamicin or isotonic sodium chloride solution.12 Both colonization and infection due to AGNB were significantly reduced. The second study in 45 patients compared gentamicin vs paromomycin sulfate plus polymyxin B.13 Again, colonization and infection caused by AGNB were effectively controlled. Although the endotracheal administration of gentamicin was better tolerated than the combination, emergence of resistant AGNB was a more serious problem in the patients receiving monotherapy compared with the combination.

The methods of aerosolization and endotracheal instillation do not take into account the pathways of colonization and infection. There is consensus that microorganisms carried in the oropharynx migrate into the lower airways, ie, the endogenous route. We found that in children with tracheotomy the exogenous route, ie, microorganisms immediately introduced into the lower airways and bypassing the oropharynx, substantially contributed to the colonization and infection of the lower airways in patients with tracheotomies. Our 5-year study using longitudinal serial sampling of both the oropharynx and lower airways enabled us to distinguish the endogenous route from the exogenous route. In addition, in comparing the oropharyngeal flora on admission to the PICU and at the time of placement of a tracheotomy, primary carriage was distinguished from secondary carriage, ie, the oropharyngeal carrier state of microorganisms acquired during the stay on the PICU and respiratory ward.

This study using carriage for classifying colonization and infection in children with tracheotomies shows that about half the population acquired nosocomial, ie, respiratory ward–associated, microorganisms. The most recent meta-analysis of selective decontamination of the digestive tract in patients receiving mechanical ventilation shows that 0.5 g of a 2% paste of polymyxin B sulfate and tobramycin sulfate applied in the lower part of the cheeks 4 times a day was effective in eradicating microorganisms already present and in preventing secondary endogenous colonization and infection.14 Hygiene is indispensable for the control of exogenous colonization and infection. However, in our experience, keeping high standards of hygiene in children with, for example, cerebral palsy is not always possible, as 87% of the study population acquired microorganisms in the lower airways. The topical application of the same mixture on the tracheotomy site has been shown to be a promising method in the control of exogenous colonization and infection.15 A randomized trial evaluating topical paste applied both in the oropharynx and on the tracheotomy site compared with placebo is under way.

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Article Information

Accepted for publication February 13, 2002.

Corresponding author and reprints: Pradeep Morar, MD, 21a Tanhouse Ln, Parbold WN8 7HG, Lancashire, England (e-mail: paddy@morarp.freeserve.co.uk).

References
1.
Bartlett  JGFaling  LJWilley  S Quantitative tracheal bacteriologic and cytologic studies in patients with long-term tracheostomies. Chest.1978;74:635-639.
2.
Niederman  MSFerranti  RDZiegler  AMerrill  WWReynolds  HY Respiratory infection complicating long-term tracheotomy: the implication of persistent gram-negative tracheobronchial colonization. Chest.1984;85:39-44.
3.
Palmer  LBDonelan  SVFox  GBellemore  EGreene  WH Gastric flora in chronically mechanically ventilated patients: relationship to upper and lower airway colonization. Am J Respir Crit Care Med.1995;151:1063-1067.
4.
Niederman  MSMantovani  RSchoch  PPapas  JFein  AM Patterns and routes of tracheobronchial colonization in mechanically ventilated patients: the role of nutritional status in colonization of the lower airway by Pseudomonas species. Chest.1989;95:155-161.
5.
Rogers  JH Tracheostomy and decannulation.  In: Kerr  AG, ed. Scott-Brown's Otolaryngology.Vol 6.6th ed. London, England: Butterworths; 1997:471-486.
6.
Tym  GM Home tracheostomy care.  In: Kerr  AG, ed. Scott-Brown's Otolaryngology.Vol 6.6th ed. London, England: Butterworths; 1997:487-494.
7.
Torres  AMartos  ADe La Bellacasa  JP  et al Specificity of endotracheal aspiration, protected specimen brush, and bronchoalveolar lavage in mechanically ventilated patients. Am Rev Respir Dis.1993;147:952-957.
8.
Marquette  CHGeorges  HWallet  F  et al Diagnostic efficiency of endotracheal aspirates with quantitative bacterial cultures in intubated patients with suspected pneumonia: comparison with the protected specimen brush. Am Rev Respir Dis.1993;148:138-144.
9.
van Saene  HKFDamjanovic  VMurray  AEde la Cal  MA How to classify infections in intensive care units: the carrier state, a criterion whose time has come? J Hosp Infect.1996;33:1-12.
10.
Lepper  MHKofman  SBlatt  N  et al Effect of eight antibiotics used singly and in combination on the tracheal flora following tracheotomy in poliomyelitis. Antibiot Chemother.1954;4:829-843.
11.
Palmer  LBSmaldone  GCSimon  SRO'Riordan  TGCuccia  A Aerosolized antibiotics in mechanically ventilated patients: delivery and response. Crit Care Med.1998;26:31-39.
12.
Klastersky  JHuysmans  EWeerts  DHensgens  CDaneau  D Endotracheally administered gentamicin for the prevention of infections of the respiratory tract in patients with tracheostomy: a double-blind study. Chest.1974;65:650-654.
13.
Klastersky  JHensgens  CNoterman  JMouawad  EMeunier-Carpentier  F Endotracheal antibiotics for the prevention of tracheobronchial infections in tracheotomized unconscious patients: a comparative study of gentamicin and aminosidin–polymyxin B combination. Chest.1975;68:302-306.
14.
Silvestri  LMannucci  Fvan Saene  HK Selective decontamination of the digestive tract: a life saver. J Hosp Infect.2000;45:185-190.
15.
Morar  PMakura  ZJones  A  et al Topical antibiotics on tracheostoma prevents exogenous colonization and infection of lower airways in children. Chest.2000;117:513-518.
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