Nosocomial pulmonary infections

9 Nosocomial pulmonary infections M. HEMMER

Nosocomial pneumonia is defined as a lower respiratory tract infection neither present nor incubating at the time of hospital admission. Diagnosis is based on clinical and radiological findings confirmed by microbiological examination (Centers of Disease Control, 1988). Nosocomial pulmonary infection is a well recognized and frequent complication with a high mortality rate in ventilated intensive care unit (ICU) patients. PATHOGENESIS AND CLASSIFICATION OF NOSOCOMIAL PULMONARY INFECTIONS Bacteria that cause respiratory infection may be inoculated into the respiratory tract by inhalation, aspiration of oropharyngeal or gastrointestinal contents, haematogenous spread from distant foci, or by direct extension from contiguous infectious sites. The first two routes of inoculation are by far the most frequent in ICU patients. In healthy subjects, antibacterial lung defence mechanisms efficiently inactivate even large numbers of pathogenic organisms through the action of the mucociliary system, alveolar macrophages, polymorphonuclear leukocytes, and humoral immune factors. When the inoculum is particularly massive or virulent or when host defences are compromised by critical illness the body's bactericidal mechanisms become exhausted and bacterial proliferation occurs (La Force, 1981; Johanson, 1984). The way in which bacteria enter the lung may also play a role in the development of infection. It has been demonstrated experimentally that lung bacterial defences perform less well when presented with bacteria in a fluid bolus than when bacteria are deposited as small particles of aerosol (Berendt et al, 1978). Factors such as hypoxia, alveolar oedema, mechanical and inflammatory lesions of respiratory tract mucosa, toxic or dry gases or depletion of neutrophils, circulating antibodies and complement are known to affect adversely lung defence mechanisms (Johanson, 1984; Pennington, 1989). These factors are common in patients needing intensive care. Once established, pulmonary infection becomes a self-perpetuating process because in the areas of acute inflammation and hypoxia the bacterial defence system becomes progressively more impaired. This may be one of Bailli~re"s Clinical A naesthesiology--

Vol. 4, No. 2, September 1990 ISBN 0-7020-1465-6

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the reasons for the relative refractoriness of pulmonary infections to antimicrobial therapy (Johanson, 1984; Tobin and Grenvik, 1984). Bacteria in the ICU environment and on contaminated equipment can be transferred to the patient by the airborne route or on the hands of personnel. Nosocomial pulmonary infection that develops by this way of transmission is classified as exogenous. However, in the majority of cases the pathogenesis of nosocomial pneumonia is endogenous, which means that infecting microorganisms, most frequently aerobic gram-negative bacilli (AGNB), belong to a patient's own bacterial flora and are either transiently (by carriage) or permanently (by colonization) present in the gut, stomach and oropharynx (Redman and Lockey, 1967; Johanson et al, 1969; Bryant et al, 1972; Johanson et al, 1972; Schwartz et al, 1978). The steps in the pathogenesis of endogenous pulmonary infection are: 1. 2. 3. 4. 5.

oropharyngeal and intestinal carriage of bacteria; impairment in colonization defence, bacterial colonization of oropharynx and stomach; aspiration of a bolus of colonized oropharyngeal or gastric secretions into the tracheobronchial tree; impairment of lower-airway colonization defence, bacterial colonization of lower respiratory tract; interaction with pulmonary defence mechanisms.

Bacterial colonization of the respiratory tract of critically ill patients plays an essential role in the pathogenesis of nosocomial pneumonia. The degree of impairment of cellular and humoral lung defence mechanisms determines whether pneumonia will follow respiratory tract colonization. The major source of bacteria that may colonize the patient's oropharynx, stomach and respiratory tract are AGNB of their own intestinal flora. The colonized stomach may serve as a reservoir and a conduit of bacteria towards the oropharynx and the trachea (Atherton and White, 1978). Pulmonary infections due to patient's residential flora at admission are sometimes classified as 'primary endogenous pneumonia'. When the patient's colonization defence mechanisms become deficient, the gut becomes colonized with hospital-acquired, often multiresistant AGNB, which may be environmental or transmitted from other colonized patients. These microorganisms are rapidly transferred to the stomach and oropharynx and may be aspirated into the lungs (Van Uffelen et al, 1984). Pulmonary infections caused by hospital-acquired microorganisms transferred to the lungs by the endogenous route are sometimes classified as 'secondary endogenous pneumonias'. Generally it has been considered that the clinical signs of ICU-acquired pneumonia do not appear until at least 48 hours after admission. Therefore, nosocomial pulmonary infection is often defined as, 'pneumonia developing after 48 hours of admission'. Recently another classification system dividing nosocomial pulmonary infections into 'early onset pneumonia' and late onset pneumonia', with day four as the cut off, was proposed (Langer et al, 1987). This classification is based on the fact that nearly half the acquired pneumonias develop between the first and the fourth day after admission to

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the ICU. Early onset pneumonias are probably due to a more massive aspiration of bacteria-loaded oropharyngeal or gastric contents soon after admission to ICU or at the moment of endotracheal intubation, especially in patients with impaired airway reflexes and severely altered lung defence mechanisms. This type of acquired pulmonary infection frequently occurs in polytrauma and unconscious patients and is more often due to a patient's 'normal flora' than to colonizing gram-negative bacteria. Oropharyngeal, gastrointestinal and tracheal defence mechanisms against bacterial colonization

Carriage is defined as the presence of the same microorganisms in any concentration in at least two consecutive salivary or faecal specimens over at least one week. Colonization can be defined as the prolonged presence of bacteria at a site not normally occupied in the absence of a significant host immune response or adverse effects on the host. The oropharynx of a healthy individual contains a large number of endogenous and community-acquired bacteria--some are permanent residents (anaerobes and ~ haemolytic streptococci) and some are community-acquired (Streptococcus pneumoniae, Hemophilus influenzae, Branhamella catharralis, Neisseria sp and Staphylococcus aureus). This normal flora lives in symbiosis with the host and inhibits the growth of other microorganisms by bacterial interference: competitive adherence to epithelial cells, production of inhibitory substances and specific substrate utilization which creates a physicochemical milieu favourable for 'normal' bacteria and harmful for 'abnormal' bacteria. One of the main characteristics of the 'normal flora' is its adherence specificity, which means that specific organisms bind to precise anatomical sites. It permits the contingency of areas with massive growth of bacteria to sterile zones (for example, the orotracheal cavity with its normal flora is contiguous to the sterile respiratory tract distal to the vocal cords). Oropharyngeal carriage of gram-negative bacteria (Enterobacteriaceae, Pseudomonoaceae) is uncommon in healthy individuals with intact defence barriers (Johanson, 1984; Hart, 1988). The defence mechanisms of the oropharyngeal cavity against colonization are: 1. 2. 3. 4.

5.

physical clearance (mucociliary activity of nasal mucosa, chewing, swallowing); specific adherence properties of buccal epithelial cells (presence of fibronectin which covers epithelial cell surface receptors for AGNBinhibiting bacterial-epithelial cell adherence); rapid mucosal cell turnover and desquamation; specific action of oral secretions (presence in the saliva of secretory immunoglobulin A (IgA) and antileukoprotease (which inhibit adhesive activity of AGNB), presence of lysozyme and lactoferrin (which exert antibacterial activity) ); colonization resistance due to previously discussed mechanisms of

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interbacterial inhibition (La Force et al, 1976; Woods et al, 1981; Niederman et al, 1986; Dal Nogare et al, 1987; Pennington, 1989). The gastrointestinal tract is the major source of endogenous microorganisms. The oesophagus, stomach, duodenum and jejunum are relatively free of bacteria (although yeasts and anaerobic bacteria are occasionally cultured from the stomach) but the terminalileum, colon and rectum harbour an enormous load of microorganisms. The terminal colon contains 1011-1012 colony-forming units (cfu) of anaerobic organisms per gram of faeces with four predominant genera: Bacteroides, Veillonella, Eubacterium and Bifidobacterium, and 10l~ cfu/g of faeces of aerobic Enterobacteriaceae, with Escherichia coli and Enterococcus sp. predominating. Other Enterobacteriaceae (Klebsiella sp., Proteus sp., MorganelIa sp. and Enterobacter sp.) are found in much smaller numbers and carriage of Pseudomonaceae is unusual in healthy subjects. The defence mechanisms of the gastrointestinal tract against colonization with 'abnormal' flora and against dissemination of bacteria are: 1. 2. 3. 4. 5.

6.

physical clearance (normal peristalsis with a rapid transit time in the upper portions of the gastrointestinal tract); secretory function (acidity of gastric juice which is the most important barrier against transference of bacteria from the gastrointestinal tract to the oropharynx and vice versa; antibacterial properties of the bile); specific mucosal adherence properties (presence of endothelial cell receptors for bacteria and endotoxins, rapid mucosal cell turnover, presence of IGA in mucus and bile); specific intestinal immunity (phagocytic, humoral and cell-mediated); colonization resistance due to bacterial interference mechanisms: the presence of an intact anaerobic flora of the gut seems to be of great importance in prevention of overgrowth by 'abnormal' bacteria (Van den Waaij et al, 1971); the translocation of the gastrointestinal tract bacteria by the haematogenous route is prevented by the phagocytic function of the liver Kuppfer cells, which remove bacteria and endotoxin of intestinal origin from the portal circulation (Matuschak and Rinaldo, 1988).

Mechanisms of colonization defence of the tracheobronchial tree include the cough reflex, activity of the mucociliary escalator and the integrity of the epithelial surface with presence of secretory IgA, which inhibits bacterial adherence. A normal lower respiratory tract removes bacteria efficiently, even after increased exposure. At the alveolar level the main host defence mechanisms that kill and remove bacteria are phospholipid surfactant and proteins--immunoglobulins and complement--in the alveolar lining and phagocytic cells--alveolar macrophages and polymorphonuclear neutrophils (Pennington, 1989). Factors predisposing to colonization of the respiratory tract infection with gram-negative bacteria In critically ill patients with impaired oral, gastrointestinal and tracheal

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colonization defences the number of colonizing gram-negative bacteria increases rapidly following admission to an ICU (Johanson et al, 1969). Usually, oropharyngeal colonization with gram-negative bacteria occurs first and precedes infection with the same microorganisms (Schwartz et al, 1978). However, it has been demonstrated recently that mechanically ventilated patients may have different patterns of upper- and lower-airway colonization and that there are three ways in which bacteria can be transmitted: oropharynx to trachea; oropharynx to stomach and trachea and stomach to trachea and oropharynx. Primary colonization of the trachea with gram-negative bacteria without first colonizing the oropharynx and stomach was also reported (Pingleton et al, 1986). A possible explanation of these clinical observations is that separate colonization of the oropharynx, the stomach and the trachea is a marker of multiple deficits in the host defences with different degrees of impairment at the three sites. An important mediator in colonization is increased bacterial adherence to epithelial cells. Specific colonization patterns for specific organisms at different sites have been reported with preferential colonization of the oropharynx with Enterobacteriaceae and the trachea with Pseudomonaceae (Ramphal et al, 1980; Niederman et al, 1983). Oral secretions of severely ill patients have been shown to contain proteolytic enzymes (in particular neutrophil elastase), which digest cell surface fibronectin and uncover receptors for bacterial binding (Dal Nogare et al, 1987). Various clinical factors related to the severity of the underlying disease, such as uraemia, dehydration, malnutrition and tracheal intubation, have been shown to increase the density of cellular receptors for bacterial adhesins on the surface of respiratory tract epithelial cells (Johanson et al, 1979; Niederman et al, 1984; Ramphal et al, 1980). Although modification of the adhesive properties of endothelial cells plays a major role, other factors are also important in the development of colonization (Valenti et al, 1978). Coma and impaired airway reflexes affect clearance mechanisms of the oropharynx and the tracheobronchial tree (Huxley et al, 1978). Paralytic ileus or intestinal obstruction are associated with decreased intestinal mobility and mucus production and lead to the loss of gastric acidity with subsequent bacterial overgrowth of the stomach. Therapeutic interventions may also favour colonization with gramnegative bacteria. Oral or nasotracheal intubation permits bacterial leakage around the cuff to the trachea and damages the ciliated epithelium (Spray et al, 1976). Gastric tubes produce mucosal lacerations and facilitate the retrograde spread of bacteria from the stomach. Peptic ulcer prophylaxis with antacids or histamine type 2 antagonists and early enteral feeding increases the pH of gastric secretions, leading to bacterial colonization of the stomach, and these have been reported as risk factors for the development of nosocomial pneumonia (Ruddel et al, 1980; Du Moulin et al, 1982; Pingleton et al, 1986). Systemic antibiotics alter the mechanisms of bacterial interference by killing the 'normal flora' that controls pathogenic bacterial growth (Sprunt et al, 1971; Yoshioka et al, 1982). In addition, long-term administration of

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antibiotics may have an adverse effect on host immune responses (Hauser and Remington, 1982). Prolonged Use of corticosteroids has been shown to depress the function of the alveolar macrophages (Hunninghake and Fauci, 1977). RISK FACTORS FOR DEVELOPMENT OF NOSOCOMIAL PNEUMONIA

In 1981 the US study on the Efficacy of Nosocomial Infection Control (SENIC) reported on the joint association of multiple risk factors with the occurrence of nosocomial infections and produced a 'risk tree model' for different types of infection (Hooton et al, 1981). The factors found to be highly important for the development of nosocomial pneumonia were patient's intrinsic risk (as reflected by the diagnosis and type of surgical procedure), duration of operations, anatomical site of surgical procedures and immunosuppressive therapy. However, these data were obtained from patients hospitalized in 197.0 when respiratory support was not yet widely used, and the role of mechanical ventilation was not evaluated. Since that time, many specific risk factors have been identified in ventilated ICU patients and a multivariate statistical approach is used in several recent studies to analyse the independent risk factors for the development of nosocomial pulmonary infections (Craven et al, 1986; Celis et al, 1988). The following risk factors have been identified as significantly related to the development of nosocomial pneumonias.

Patient-related factors 1.

2. 3. 4. 5. 6. 7.

Severity of underlying disease (which was reported in all studies as the most important independent risk factor) (Garibaldi et al, 1981; Haley et al, 1981a; Hooton et al, 1981; Gross et al, 1983; Celis et al, 1988; Fagon et al, 1988). Presence of impaired airway reflexes and coma (Langer et al, 1987; Celis et al, 1988). High-volume aspiration of oropharyngeal or gastrointestinal contents (Celis et al, 1988). Surgical pathology and thoracoabdominal location of surgery (Garibaldi et al, 1981; Haley et al, 1981a; Hooton et al, 1981; Bryan and Reynolds, 1984). Age >65 years (Haley et al, 1981; Hooton et al, 1981; Fagon et al, 1988). Male sex (Garibaldi et al, 198i; Hooton et al, 1981). Presence of chronic obstructive pulmonary disease (COPD), smoking habit, alcoholism (Celis et al, 1988).

Therapy-related factors 1.

Respiratory tract instrumentation (intubation, tracheostomy) (Cellis et al, 1988).

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2.

Prolonged mechanical ventilation (Celis et al, 1988; Fagon et al, 1988; Langer et al, in press). 3. Frequent (every 24 h) changes of ventilatory circuit--it is possible that contamination of respiratory devices may increase with the frequency of manipulation (Craven et al, 1986). 4. Routine use of cimetidine for stress ulcer prophylaxis (Driks et al, i 1987). 5. Use of steroids and immunosuppressive therapy (Haley et al, 1981a). 6. Presence of an intracranial pressure monitoring device (Craven et al, 1986). This may be an indicator of the patients with more severe cerebral pathology. 7. Duration of hospital and ICU stay (Garibaldi et al, 1981; Haley et al, 1981a). 8. Duration of surgery (Garibaldi et al, 1981; Haley, 1981a). 9. Previous antibiotic therapy (Fagon et al, 1988).

Seasonal factors An increased risk is reported in the autumn and winter (Craven et al, 1986). DIAGNOSIS OF NOSOCOMIAL PNEUMONIA Diagnosis of nosocomial pulmonary infection is based on clinical, radiological and bacteriological examination. Fever, leukocytosis, ausculatory tales, new onset of purulent tracheobronchial secretion, new and progressive radiological infiltrates, and the presence of pathogenic bacteria in respiratory secretions are the usual criteria for pulmonary infection. However, the reliability of these criteria in patients who require intensive therapy is uncertain. Recently, Filice et al (1989) have shown that fever and leukocytosis have a very low predictive value for diagnosis of pneumonia. Severe infection is sometimes associated with leukopaenia, and fever and leukocytosis are virtually absent in patients receiving immunosuppressive treatment. Therefore, in the new CDC (Centers of Disease Control) definitions for nosocomial infections, fever and leukocytosis are not mentioned as prerequisites for pneumonia (Centers of Disease Control, 1988). Pulmonary infiltrates, even when associated with impaired gas exchange, may be due to pulmonary embolism, persistent atelectasis, lung contusion, congestive heart failure or purulent tracheobronchitis. New imaging techniques, in particular thoracic computed tomography, have been reported to improve the specificity of radiological diagnosis (Holzapfel et al, 1988). The presence of pathogenic bacteria in the tracheobronchial tree due to respiratory tract colonization occurs in the majority of ventilated patients. Regular bacteriological assessment of tracheobronchial secretions was suggested to facilitate the diagnosis of nosocomial pneumonia (Goldenheim and Kazemi, 1984). An increase in the density of potential pathogens on a gram stain, together with positive culture results and appropriate clinical

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and radiological signs should provide an indication of pulmonary infection. A simple method of sampling tracheobronchial secretions in intubated patients by a sterile catheter blindly wedged in the peripheral bronchi was described by Matthew et al (1977). However, in some categories of ICU patients, especially those presenting with acute respiratory distress syndrome (ARDS), the diagnosis of nosocomial pneumonia is particularly difficult. All patients with ARDS have diffuse radiological infiltrates, colonized proximal airways and biological signs suggesting infection or inflammation. Andrews et al (1981) compared the prediction of nosocomial pneumonia, based on clinical findings and bacteriological examination of tracheobronchial aspirate with postmortem lung histology in 24 ARDS patients: 29% of cases were misdiagnosed; false-negative diagnosis was made in one-third of patients who had pneumonia and false-positive diagnosis was made in one-fifth of patients who had diffuse lung injury only. Misdiagnosis of nosocomial pneumonia may delay the onset of antimicrobial therapy in patients with unrecognized pulmonary infection or lead to inadequate or unnecessary treatment in others, with the danger of superinfection by resistant pathogens and exposure to antibiotic toxicity. Therefore, it is very important to develop sensitive and specific diagnostic tests. Several authors have reported that microbiological examination of tracheobronchial aspirate is often inaccurate because of contamination by the oropharyngeal bacteria and the uncertainty whether the sampled specimen really originates from the infected area (Johanson et al, 1972; Bartlett et al, 1978). However, Salata and colleagues (1987) have postulated that serial quantitative cultures of tracheobronchial aspirate and graded gram stains of neutrophils, bacteria and intracellular organisms, together with a systematic search for elastin fibres at microscopic examination may provide a means for early diagnosis of nosocomial pneumonia. A positive culture of blood or pleural fluid is considered to be a confirmation of the diagnosis, although positive blood cultures may also originate from other infected sites. The reliability of open fibreoptic bronchoscopic sampling has also been evaluated, but significant contamination of the aspirate with oropharyngeal or tracheal microorganisms has been reported with this type of sampling (Bartlett et al, 1976). Other, more specific, techniques developed recently include transtracheal puncture, transbronchial biopsy, transthoracic needle aspiration, and open lung biopsy. These are invasive, have frequent complications and cannot be used routinely in ventilated, critically ill patients (Bartlett et al, 1977; Pennington, 1989). To obtain an uncontaminated distal sample, a catheter brush protected by a telescoping double sheath with a polyethylene glycol plug that may be passed through a fibre0ptic bronchoscope and directed towards the area of suspected infection was developed by Wimberley et al (1979, 1982). Strict adherence to the described sampling procedure, rapid processing of the specimen and performance of quantitative cultures are necessary to obtain an accurate diagnosis with this technique. This method was first validated in animal models (Higuchi et al, 1982; Moser et al, 1982) and in patients with

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community-acquired pneumonia (Pollock et al, 1983). Pollock et al have demonstrated that a bacterial colony count of t> 103 cfu/ml in suspended secretions collected with the protected specimen brush (PSB) permitted the diagnosis of bacterial pneumonia in patients without endobronchial structural abnormalities but false-positive results were frequently observed in patients with chronic tracheobronchitis. In 1984, Chastre et al validated the use of quantitative cultures of PSB samples for the diagnosis of nosocomial pneumonia in ventilated patients. PSB, histological examination of lung tissue, and bacterial culture were performed immediately after death in 24 ICU patients. The culture of PSB samples with i> 103 cfu/ml identified the six cases of histologically proven pneumonia and correlated well with the microorganisms present in the lung tissue cultures in concentrations greater than 10"cfu/ml. The results of this study encouraged the widespread use of PSB in the diagnosis of nosocomial pneumonia, and as a guide to the choice of antimicrobial therapy. However, the fibreoptic PSB technique, although specific and sensitive, is not easily repeatable at the bedside. It can also cause complications, such as pneumothorax, haemothorax, bronchial haemorrhage and episodes of severe hypoxia (Torzillo et al, 1985; Torres et al, 1988). The results of quantitative cultures require at least 24-48 hours and PSB cannot guide the initial antimicrobial therapy, because the direct microscopic examination is difficult to perform. It should also be emphasized that there is no absolute threshold for quantitative cultures to separate colonization and infection, and that 20-30% of false-positive results with PSB have been reported (Fagon et al, 1988). Moreover, as the protected brush samples a very small area of the lung, false-negative results due to the incorrect positioning of the catheter may be obtained. False-negative results have also been reported in patients with ongoing antimicrobial therapy (Chastre et al, 1984, 1989). Johanson et al (1988b) have recently demonstrated in an animal model that bronchoscopic bronchoalveolar lavage (BAL) provided better quantitative and qualitative evaluation of lung microbiology than PSB, especially in polymicrobial pulmonary infections. The diagnostic value of BAL, performed by various protected and unprotected techniques, some of them very promising, has been evaluated in several human studies (Table 1). Chastre et al (1989) compared PSB with BAL and concluded that the two procedures used together provided complementary results. Presence of more than 7% of cells containing intracellular bacteria in cytocentrifuge preparations obtained from BAL fluid identified patients with pneumonia, and the coloration and morphologic properties of these bacteria correlated well with the results of quantitative cultures from PSB samples and could be used as a reliable guide for immediate antimicrobial therapy. BAL and PSB combined together, offered the overall diagnostic accuracy of 97% and no false-negative results were reported. However, both PSB and bronchoscopic BAL are invasive and require special expertise. It has not been demonstrated that such sophisticated techniques are indispensable for the diagnosis of all types of nosocomial pulmonary infections in ventilated patients. Recently, Papazian et al (1989)

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reported a 93% agreement between the organisms isolated by PSB and blind bronchial aspiration of secretions in ventilated patients with diffuse bronchopneumonia. The search for a diagnostic approach that would be specific, sensitive, safe and cost-effectivecontinues, and several new techniques have been evaluated recently (Table 1). Further studies are necessary to determine the exact place of these techniques in clinical and bacteriological practice. BACTERIOLOGY OF NOSOCOMIAL PULMONARY INFECTIONS

The importance of AGNB as pathogens in nosocomial respiratory infections is well documented in several surveys (Johanson et al, 1972; Stevens et al, 1974). AGNB were responsible for 74% of nosocomialpneumonias reviewed in the eight-hospital Comprehensive Hospital Infections Project, 44% of episodes reported in the National Nosocomial Infection Study (Centers of Disease Control, 1979) and 46% of cases in the study by Bartlett et al (1986). In these surveys Klebsiella sp. followed by Pseudomonas sp. were the predominant pathogenic microorganisms, accounting for more than half the nosocomial pneumonias. M a n y episodes of pulmonary infection were polymicrobial. However, in these studies bacteriological diagnosis of pulmonary infection was based on the culture of sputum or tracheobronchial aspirate and the potentially pathogenic bacteria c61onizing the respiratory tract could not be differentiated from the bacteria causing nosocomial pneumonia. Two recent prospective studies from Barcelona (Jimenez et al, 1989) and Paris (Fagon et al, 1988) have used a more specific bacteriological diagnostic procedure to determine the microbial aetiology of nosocomial pneumonia in ventilated patients. Both studies used fibreoptic bronchoscopy and protected brush specimens as the sampling techniques and the threshold of /> 103cfu/ml for quantitative culture was used to distinguish pulmonary infection from respiratory tract colonization. Jimenez et al (1989) reported that 86% of ventilator-acquired nosocomial pulmonary infections were caused :by AGNB with Pseudomonas aeruginosa and Acinetobacter sp. as predominant pathogens, and that gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermidis) were responsible for only 14% of pneumonias. The study of Fagon et al (1988) is the largest prospective survey of nosocomial pneumonia in which uncontaminated bacteriological specimens were examined to establish the aetiology of infection. In their patients, AGNB were recovered in 75 % of 52 episodes of nosocomial pneumonia. The predominant AGNB were P. aeruginosa, Acinetobacter sp. and Proteus sp. which together accounted for 60% of all gram-negative bacteria and 40% of all organisms isolated. Other AGNB (Hemophilus influenzae, Escherichia coli, Enterobacter cloacae, Branhamella catarrhalis, Citrobacter freundii and Legionella pneumophila) were less frequently encountered. However, there was also a high rate (52%) of episodes that included at least one gram-positive organism and Staphylococcus aureus was the most

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frequently isolated potential pathogen (20% of all isolates), followed by S.

pneumoniae. 33% of pneumonias in this series were caused by or included organisms such as streptococci other than S. pneumoniae, H. influenzae, B. catarrhalis and Corynebacterum sp. Approximately 40% of all infections involved a mixed flora with more than one potentially pathogenic bacteria. These results confirm the importance of AGNB, underscore the role of oropharyngeal microorganisms, and demonstrate the high incidence of polymicrobial flora in the aetiology of bacterial ventilator-acquired pneumonia. INCIDENCE AND TIME OF ONSET OF NOSOCOMIAL PULMONARY INFECTION During the last 20 years, knowledge of the epidemiology of nosocomial pulmonary infection has substantially increased. According to the estimate by SENIC, 0.5-1% of all hospitalized patients acquire lower respiratory tract infection and this risk is much higher in ICU patients requiring ventilatory support (Haley et al, 1981a). The reported incidence of nosocomial pneumonia in ICU varies from 7.5 to 65 % in various series in spite of the similarity of infection control procedures (Tables 2 and 3). This variation is largely a result of the different populations studied, but it may also reflect differences in the bacteriological criteria for the definition of nosocomial pulmonary infection (Tables 2 and 3). When patient populations from several recent studies are pooled and classified according to the need for respiratory support, the rate of nosocomial pulmonary infection, which is about 15% in the general ICU patient population, rises to 26% in patients who require respiratory support for 24 hours and reaches 60% or more in some series of long-term (>5 days) ventilated patients (Tables 2 and 3). Recently, Fagon et al (1989) reported that the actuarial risk of pneumonia in ventilated patients increased by 1 + 0.76% with each day of mechanical ventilation and was 6.5% at 10 days, 19% at 20 days and 28% at 30 days. On the other hand, data reported by Langer et al (1989) from the Italian Multicenter Study have shown that more than half of the cases of acquired pneumonia occur before the tenth day of mechanical ventilation and that after that time the risk of pneumonia decreases. The differences in the results of these two studies are probably explained by the different patient populations. In the Italian Multicenter Study, 55% of the population was composed of multiple trauma and postsurgical patients and frequent development of early nosocomial pulmonary infection in these two categories of patients has been reported (Caplan and Hoyt, 1981; Garibaldi et al, 1981; Martin et al, 1984; Brown et al, 1985; Stoutenbeek et al, 1986; Mock et al, 1988). PROGNOSIS AND OUTCOME OF NOSOCOMIAL PNEUMONIA It has been recognized that nosocomial pneumonia contributes to the

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morbidity of ICU patients. Haley et al (1981b) reported that acquired respiratory tract infections increased length of hospitalization by 4 to 5 days. Craig and Connely (1984) found that pneumonia caused a three-fold increase in ICU stay. In the series of Jimenez et al (1989) the mean duration of mechanical ventilation increased from 10 to 32 days when nosocomial pneumonia developed. The mortality rate of patients who develop nosocomial pneumonia varies from 31 to 76% and, in the majority of studies, is much higher than the mortality rate of non-pneumonia patients (Tables 2 and 3). Despite this high fatality rate it is not proven at present that pneumonia increases the risk of mortality in critically ill patients. In the majority of patients who die with nosocomial pulmonary infection the presence of a severe coexisting disease renders the demonstration of a direct link very difficult. Gross et al in a case control study evaluated the relationship between nosocomial infections and mortality and concluded that infection was relatively unimportant in relation to outcome if the patient had a terminal diagnosis at admission (Gross et al, 1980; Gross and Antwerpen, 1983). However, among the patients whose condition was not terminal at admission nosocomial infection, and especially pneumonia, favoured a fatal outcome. This observation was supported by the study of Craven et al who reported that the rate of death due to nosocomial infections was higher in their surgical than their medical ICU, because the medical patients were older, often had a more severe underlying disease and died more frequently from other causes. In their study, the relative risk of fatality was increased three-fold in patients who acquired a nosocomial infection. Caplan and Hoyt (1981) and Stoutenbeek et al (1986) reported a significant mortality from nosocomial pneumonia in multiple trauma patients. In this type of patient the risk of fatality due to trauma itself is known to decrease sharply after the first 48 hours, but the impairment of defence mechanisms against colonization and infection may persist for longer periods. The Italian Multicenter Study reported that ICU-acquired pneumonia was a highly significant independent risk factor for death in critically ill ICU patients (Mosconi et al, personal communicatioin). In contrast to those results, Craven et al, who analysed the risk factors for fatality in ventilated patients, found that although ventilator-acquired pneumonia was related to patients' fatality in univariate analysis it was not present among the factors independently related to death after multivariate analysis (Craven et al, 1986, 1988). Further studies in selected groups of ICU patients with similar pathologies and with precisely defined diagnostic criteria for pulmonary infection are necessary to determine the real influence of nosocomial pneumonia on mortality. A recent study, from the Hospital Clinic of Barcelona analysed the factors that influence the prognosis of nosocomial pneumonia in a general hospital population (Celis et al, 1988). Age over 60 years, an ultimately or rapidly fatal underlying condition, acute respiratory failure, bilateral lung infiltrates, identification of high-risk bacteria (Pseudomonas sp., Enterobacteriaceae, S. faecalis, S. aureus, Candida sp., Aspergillus sp. and episodes of poly-

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bacterial pneumonia) and inappropriate antibiotic treatment were selected by stepwise logistic regression analysis as factors independently worsening the prognosis. This relationship between the mortality from pneumonia and the aetiologic agent have been confirmed by other authors. Bryan and Reynolds (1984) reported that the presence of bacteraemic pneumonia, especially if S. aureus, K. pneumoniae and P. aeruginosa were involved, identified a patient population at high risk of death. Stevens et al (1974) reported a 21% increase in mortality when P. aeruginosa was the causative agent. In the study of Fagon et al (1988), 87% of patients with ventilator-acquired pneumonia that included P. aeruginosa or Acinetobacter sp. died, whereas only 55% of patients with pneumonia caused by other organisms died. Moreover, in their study prior antimicrobial therapy significantly increased the rate of pneumonia caused by P. aeruginosa or Acinetobacter sp. and the frequency of methicillin-resistant Staphylococcal infections. PREVENTION OF NOSOCOMIAL PNEUMONIA The first attempts at prevention of nosocomial pulmonary infections concentrated on environmental sources of infection, such as contaminated sinks and respiratory devices. The classical studies of Reinarz et al (1965) elucidated the role of contaminated nebulizers generating microaerosols containing large numbers of pathogenic bacteria and delivering this inoculum to the terminal bronchioli. Since that time the mainstream nebulizers have been replaced by cascade humidifiers filled with sterile water and the general use of disposable nebulizing devices has been introduced. The role of endotracheal tubes and ventilator circuits in the development of pulmonary infection was also studied. Craven et al (1982) reported that there was no significant increase in inspiratory gas contamination or tubing colonization when ventilator circuits were changed every 48 hours instead of every 24 hours. This observation was confirmed by Comhaire and Lamy (1981) who reported that colonization of endotracheat tubes in ventilated patients occurred earlier than contamination of ventilator circuits and that the patient may be the source of contamination of the respiratory tubing. Sotille et al (1986) have recently demonstrated that in intubated patients the inner lumen of polyvinyl chloride endotracheal tubes is rapidly covered by a biofilm of bacterial aggregates surrounded by extracellular polysaccharides. The clumps of this layer can be easily dislodged by the suction catheter into the distal bronchi and thus inoculate the lung. Such adhesive colonization of biomaterials by bacteria producing a polysaccharide substance is now considered to be a major factor in human infections related to indwelling devices. Contaminated water condensate in ventilator tubing may also cause pulmonary infection if it is aspirated into the lungs. Craven et al (1984) have reported that the bacteria isolated from the condensate correlated well with patients' oropharyngeal flora, which was probably the primary source of the

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contaminating microorganisms. They recommended frequent emptying of the tubing and handling of the condensate as infectious waste. Careful positioning of the limbs of the respiratory circuit and use of water traps should prevent aspiration of the condensate. There is much evidence that nowadays, due to better routine infection prevention (better sterilization procedures, more frequent hand washing, more general use of protective gowns and gloves, more careful handling of contaminated bodily fluids, use of exhalation line filters and water traps), contamination of respiratory devices no longer plays a significant role in endemic pulmonary infection (Cross and Roup, 1981; Lynch et al, 1987). However, in spite of all preventive measures, epidemic outbreaks of nosocomial pneumonia can still be traced to exogenous environmental sources. Since bacterial colonization has an essential role in the pathogenesis of nosocomial pneumonia, prophylactic strategies aimed at eliminating endogenous sources of bacteria have been proposed. The first attempt to prevent upper-airway colonization by using topically administered antibiotics was made in 1954 in tracheotomized patients during an epidemic of poliomyelitis (Lepper et al, 1954). More recently, when the importance of airway colonization in the pathogenesis of nosocomial pulmonary infection was recognized, this approach was introduced for the prevention of pneumonia in critically ill patients. In 1973 Klastersky et al reported that endotracheal bolus injection of gentamicin decreased the incidence of respiratory tract colonization and pulmonary infection in tracheotomized neurosurgical patients. In their study the mortality rate of gentamicin-treated patients (18%) was significantly lower than the control group (58%). There were no deaths attributed to sepsis in the test group, whereas half of the deaths in the control group were caused by infection. The use of systemic antibiotics was also significantly reduced in gentamicin-treated patients. However, the study was not well controlled (open, non-randomized, with test group followed by a subsequent control group), which may have influenced the results. Moreover, a significant increase of gentamicin-resistant strains in tracheobronchial aspirates of gentamicin-treated patients was reported. Klick et al (1975) conducted a prospective, double-blind study with polymyxin aerosol prophylaxis versus placebo, administered in alternating two month cycles in 744 consecutive patients admitted to the RespiratorySurgical unit of the Beth Israel Hospital in Boston between 1972 and 1974. Polymyxin B was selected for topical administration because of its high tissue-binding capacity, poor absorption through intact mucosa and broad spectrum against gram-negative microorganisms. Topical administration of polymyxin B spray to the posterior oropharynx and trachea significantly reduced the incidence of upper-airway colonization. In this study a significant decrease in the incidence of nosocomial pulmonary infection in the test group was reported (8% versus 48% in placebo group), particularly in pneumonias due to Pseudornonas sp. (0.8% in test group versus 4.6% in placebo group). In spite of the decreased incidence of pneumonia, the overall mortality rate remained unchanged (12%), the mortality rate due to pneumonia was not significantly different in both groups (17% in the test

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group, 22% in the placebo group) and there was no reduction in the use of systemic antibiotics in the polymyxin-treated patients. However, a striking difference in the organisms causing pulmonary infection was observed. In the placebo group the majority of nosocomial pneumonias were due to Pseudomonas species, whereas in the test group polymyxin-resistant gramnegative and gram-positive bacteria were most common. A subsequent study by Feeley et al (1975) in the same RespiratorySurgical ICU evaluated the effect of continuous administration of polymyxin B aerosol in 292 patients admitted between 1974 and 1975. The incidence of nosocomial pneumonia in this group was reduced to 3.8% and Pseudomonas aeruginosa was responsible for only 0.3% of pulmonary infections. However, 91% of pneumonias were due to polymyxin-resistant microorganisms (Proteus sp., Proteus maltophilia, Morganella sp., Pseudomonas cepacia, Flavobacterium sp., Serratia sp., and Enterococcus faecalis). The overall m9rtality rate (12%) did not differ from the earlier study but the mortality rate for acquired pneumonia was much higher (64%). Massive emergence of polymyxin-resistant microorganisms and failure of reduction of mortality related to nosocomial pneumonia led the authors of the study to the conclusion that 'continuous use of polymyxin B aerosol appears to be a dangerous form of therapy'. In spite of those side-effects of the prophylactic use of polymyxin aerosol in humans several animal studies continued to assess the efficacy of this form of preventive therapy (Crouch et al, 1984). Recently, Johanson and his collaborators (1988a) compared various regimens of antimicrobial agents applied topically with and without the addition of systemic antibiotics and concluded that the regimens that combined topical polymyxin B, topical gentamicin or the two agents together along with intravenous penicillin were highly successful in preventing nosocomial pneumonia in baboons with severe lung injury ventilated for 7-10 days. They postulated that intravenous antibiotics eliminated endogenous oropharyngeal flora of the baboons and topical polymyxin and gentamicin prevented oropharyngeal and tracheal colonization with AGNB. They also observed the emergence of po!ymyxin- and gentamicin-resistant AGNB which, however, did not achieve high concentrations in the lung tissue during the time of the trial. They proposed to apply this type of preventive strategy in short-term ventilated patients but warned against long-term use of prophylactic regimens. A similar strategy, although directed primarily at the prevention of oropharyngeal and gastric colonization, was proposed by the Groningen group in 1983 (van Saene, 1983). Their prophylactic protocol, similar to the regimens used in granulocylopaenic patients, is based on the concept of selective decontamination of the digestive tract (SDD). The objective of SDD is to eliminate the AGNB and yeasts in the oropharynx and gut by non-absorbable antibiotics whilst retaining unaltered anaerobic flora which, by the phenomenon of colonization resistance, prevent overgrowth with hospital-acquired, often resistant strains. In the original Groningen protocol, systemic antibiotics are given together with the topical agents for the first 4 days. The systemic antibiotics are given to eliminate the endogenous flora

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before selective decontamination is achieved and at the same time to cover any incubating 'early' infections that may develop from contaminated wounds or from aspiration of oropharyngeal contents, vascular or bladder catheterization and emergency surgery. A mixture of polymyxin E, amphotericin B and tobramycin is used in the form of a paste for oropharyngeal decontamination, the gut is selectively decontaminated by the same antibiotics administered through the gastric tube and cefotaxime has been selected as the systemic antibiotic. The combination of both polymyxin E and tobramycin was proposed because tobramycin covers the bacterial strains intrinsically insensitive to polymyxin E (e.g. Proteus and MorganeIla sp.). Cefotaxime was chosen because of its broad spectrum of activity, good pharmacokinetic properties and therapeutic safety. Since 1984, the results of several clinical trials of the SDD have been reported. Stoutenbeek et al (1984, 1986, 1987) were the first to use this method of prevention in ICU patients. In their studies the overall infection rate in trauma patients was reduced from 81 to 16% and the rate of nosocomial pulmonary infection decreased from 59 to 8% with SDD prophylaxis. However, their results were marred by the fact that the control group was a historical one and factors other than SDD may have influenced the changes in infection rate. Ledingham et al (1988) used the same prophylactic protocol, which they called a selective parenteral and enteral antisepsis regimen (SPEAR), in a general ICU population. The efficacy of SPEAR was tested in consecutive treatment and control groups. There was a substantial decrease in colonization with AGNB and in the incidence of acquired infection (from 24 to 10 %) with a decrease in the rate of nosocomial pneumonia from 11 to 2 %. Recently, four prospective, randomized studies evaluated the efficacy of different types of SDD regimen in ICUs. The first two were performed in surgical and multiple trauma patients needing long-term ventilation. Kerver et al (1988), using the Groningen protocol, reported a decrease in the rate of nosocomial pneumonia from 85 to 12% and Unertl et al (1987) demonstrated a reduction in ventilation-acquired pulmonary infections from 70 to 21% with the use of a modified protocol in which topical tobramycin was replaced by gentamicin and prophylactic systemic antibiotics were not used. There is no general agreement on the importance of systemic antibiotic prophylaxis associated with SDD. In the study by Stoutenbeek's group systemic cefotaxime was indispensable to prevent early onset pneumonias, whereas topical decontamination alone successfully prevented late respiratory infections. In contrast, the results of the Italian multicentre randomized clinical trial (Mandelli et al, 1989) failed to demonstrate a significant reduction in the number of early onset pneumonias or in the number of deaths from pneumonia when either cefoxitin or penicillin were used as systemic prophylactic agents. Recently, the efficacy of another, less expensive; SDD protocol was tested by Ulrich et al (1989) in a general ICU population. Oropharyngeal and gastrointestinal decontamination with norfloxacin, polymyxin E and amphotericin B, together with brief systemic prophylaxis with trimethoprim,

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was reported to decrease the incidence of gram-negative respiratory infections from 44 to 6%. The rate of gram-positive infections was not altered by SDD. In contradiction to those results Brun-Buisson et al (1989) demonstrated in unselected medical ICU patients that although intestinal decontamination with neomycin, polymyxin E and nalidixic acid helped to control an outbreak of intestinal colonization and infection with multiresistant AGNB, it did not decrease the rate of endemic nosocomial infections and they therefore suggested it should not be recommended for prolonged use in ICU. It is difficult to define at present the real benefit of SDD in ICU patients. Overall decrease in mortality, considered as the ultimate goal of every therapeutic or prophylactic protocol, has not yet been demonstrated, although in certain categories of patients (acute trauma, patients with mid-range physiological severity scores--Unertl et al, 1987; Ledingham et al, 1988; Zandstra et al, 1988) improved survival rates were reported. The effect of SDD on morbidity (in terms of the length of hospital or ICU stay, duration of mechanical ventilation, use of systemic antibiotics) is controversial and a full cost-benefit analysis has never been performed. Although significant emergence of polymyxin- or tobramycin-resistant strains of AGNB has not been reported, several studies demonstrated that SDD regimens produced a change in bacterial flora with more frequent isolation of bacteria such as enterococci, coagulase-negative staphylococci and S. aureus. The long-term clinical importance of this phenomenon has still to be investigated. Nevertheless, SDD seems to be a useful method for preventing nosocomial infections and, in particular reducing nosocomial pneumonia in ventilated ICU patients. However, before its large-scale and routine use, new, randomized, placebo-controlled trials in selected and well-defined patient populations are needed to show which patients with which type of SDD regimen can benefit, how to interpret the changes in bacterial flora induced by SDD and demonstrate the effect of administration of topical and systemic antibiotics on the sensitivity and specificity of bacteriological diagnostic procedures. Another strategy for the prophylaxis of nosocomial pulmonary infections which has recently been proposed, is based on the increase of gastric colonization defences by maintaining an acid pH in the stomach and protecting the integrity of the gastric mucosa. Use of a cytoprotective substance, sucralfate, which seems to be as effective as antacids or histamine H2receptor blockers in prophylaxis against stress-induced gastric bleeding has been shown to decrease gastric colonization and to reduce substantially the incidence of nosocomial pneumonia in mechanically ventilated patients (Driks et al, 1987). However, a recent study of Flaherty et al (1988) reported that sucralfate is less effective than SDD in preventing pulmonary infection. Another interesting approach to prevention of nosocomial pneumonia is immunoprophylaxis. Encouraging reports from early trials with Pseudom o n a s aeruginosa vaccines have been reported, but those studies were performed in a small number of patients (Polk et al, 1973). Recent develop-

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ment of a hyperimmune anti-Pseudomonas globulin and of so-called crossprotective vaccines or antisera which could confer protection against a wide range of potentially pathogenic AGNB might open a new way of preventing nosocomial pneumonia (Pennington, 1989). MANAGEMENT OF NOSOCOMIAL PNEUMONIA The treatment of nosocomial pneumonia involves the use of general supportive techniques (respiratory support, tracheal and fibreoptic bronchial aspiration, and the use of intravenous antibiotics). A presumptive diagnosis can be obtained from the microscopic examination of the tracheobronchial aspirate or bronchoalveolar lavage and these results should guide initial empirical antibiotic treatment. In life-threatening pneumonias the initial treatment should cover the highly resistant AGNB (Pseudomonas sp., Acinetobacter sp.) and S. aureus. Combination regimens, generally including broad-spectrum lactam antibiotics in association with aminoglycosides are most frequently used, although some recent trials have evaluated the efficacy of single-drug therapies (Pennington, 1989). When significant oropharyngeal aspiration is suspected, the empirical regimen should cover the aerobic and the anaerobic oral flora. As soon as the definitive microbiological diagnosis is provided, the initial empirical therapy should be adapted to the bacteriological findings. Subsequent cultures are necessary to detect a possible superinfection. Throughout antimicrobial therapy the toxic effects of high doses of antibiotics should be monitored. The choice of the initial antimicrobial therapy should be based on several considerations: severity and type of the underlying disease, patients' past history (especially the presence of COPD or other chronic respiratory disease), circumstances of development of pulmonary infection (postsurgical pneumonia, early onset pneumonia in trauma patients, etc.), the prevailing microbiological flora of the ward with its resistance patterns, presence of outbreaks of pulmonary infection in the ICU or elsewhere in the hospital, and, if possible, the results of the surveillance cultures of the patient. The severity and life-threatening character of the pneumonia also influences the choice of antibiotics. CONCLUSIONS Nosocomial pneumonia is still a frequent and potentially fatal disease in ICU patients. However, development of better diagnostic methods and preventive strategies, based on a better understanding of the physiopathology of the disease together with availability of more potent antimicrobial therapies may be expected in the near future. SUMMARY

Despite major advances in intensive care therapies and techniques,

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nosocomial pneumonia remains a frequent complication in hospitalized patients. It has been shown that bacterial colonization of the oropharynx and tracheobronchial tree plays a major role in the pathogenesis of nosocomial pulmonary infection, that the bacterial sources of colonization may be both environmental and exogenous, and that the critical illness alters patient's defences against colonization and infection. Severity of underlying disease, presence of impaired airway reflexes and the use of respiratory support devices have been recognized as the most important risk factors for development of nosocomial pneumonia. New and promising prophylactic strategies and sophisticated techniques of microbiological diagnosis have recently been developed. However, many areas of controversy still exist, concerning the definitions and the classification of nosocomial pulmonary infections, the feasibility of certain diagnostic procedures and the choice of prophylactic protocols. Further advances in the diagnosis, the prevention, and the treatment of this complication require new and carefully designed studies in well-defined populations of critically ill patients. Acknowledgement The author thanks Mrs Zita Sbodio for typing and preparing the manuscript.

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