Advances in the management of pneumonia in the intensive care unit: review of current thinking J. Rello, E. Diaz and A. Rodríguez

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1 REVIEW Advances in the management of pneumonia in the intensive care unit: review of current thinking J. Rello, E. Diaz and A. Rodríguez Critical Care Department, Joan XXIII University Hospital, University Rovira i Virgili, Tarragona, Spain ASTRACT Interventions to prevent pneumonia in the intensive care unit should combine multiple measures targeting the invasive devices, microorganisms and protection of the patient. Microbiological investigation is useful for evaluating the quality of the respiratory sample, and permits early modification of the regimen in light of the microbiological findings. Once pneumonia develops, the appropriateness of the initial antibiotic regimen is a vital determinant of outcome. Three questions should be formulated: (1) is the patient at risk of acquiring methicillin-resistant Staphylococcus aureus, (2) is Acinetobacter baumannii a problem in the institution, and (3) is the patient at risk of acquiring Pseudomonas aeruginosa? Antibiotic therapy should be started immediately and must circumvent any pathogen resistance mechanisms developed after previous antibiotic exposure. Therefore, antibiotic choice should be institution-specific and patient-oriented. Keywords De-escalation therapy, review, sepsis, treatment, ventilator-acquired pneumonia Clin Microbiol Infect 2005; 11 (Suppl. 5): INTRODUCTION Ventilator-associated pneumonia (VAP) represents 80% of episodes of hospital-associated pneumonia, and the term is applied to episodes that develop in intubated or tracheotomised patients under mechanical ventilation. An artificial airway is associated with a 21-fold increase in the risk of developing pneumonia [1]. Indeed, VAP is the most frequent nosocomial infection in the intensive care unit (ICU) and is responsible for more than half of antibiotic prescriptions in the ICU. Patients with VAP have a high crude mortality rate, although the question of whether these patients would survive in the absence of the complication is controversial [2]. This article will update a former review on VAP in adult patients [3], placing particular emphasis on recent investigations. Immunocompromised patients and children are beyond the scope of this review. Corresponding author and reprint requests: J. Rello, Critical Care Department, Joan XXIII University Hospital, Carrer Dr Mallafre Guasch 4, Tarragona, Spain jrc@hjxxiii.scs.es RISK FACTORS In the National Nosocomial Infections Surveillance (NNIS) system [4], rates of VAP varied from five cases per 1000 ventilator-days in paediatric patients to 16 cases per 1000 ventilator-days in patients with thermal injury or trauma. Rates of VAP are generally higher in surgical than in medical ICU patients. Kollef [5] reported an incidence of 21.6% in cardiothoracic patients, compared with 14% in other surgical patients and 9.3% in medical patients. The cumulative risk of developing VAP is approximately 1% per day of mechanical ventilation, but it is concentrated within the first days post-intubation [6]. Intubation is the most important risk factor for developing nosocomial pneumonia [7]. Documented massive aspiration is associated with an extremely high incidence of VAP [8]. Large study populations provide the best opportunity to identify variables associated with a small increase in the probability (i.e., odds ratios (ORs) < 2) as risk factors for VAP. A prospective cohort study of 1014 ventilated patients in Canada [9] identified the following risk factors: burns (OR 5.09), trauma (OR 5.0), central nervous system disease (OR 3.4), witnessed aspiration (OR 3.25), respiratory disease Ó 2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases

2 Rello et al. Management of pneumonia in the ICU 31 (OR 2.79), cardiac co-morbidity (OR 2.72), ventilation in the last 24 h (OR 2.28), administration of paralysing agents [1,57] and antibiotic exposure (OR 0.37). In a matched cohort study [10] with 9080 patients in > 100 US hospitals, independent risk factors associated with VAP were male gender (OR 1.58), trauma [1,75], and, interestingly, intermediate deciles of severity upon admission (OR for deciles 31% to 80%). In lowseverity patients, the duration of exposure to mechanical ventilation may not be long enough for them to acquire VAP, whereas high-severity patients may die before developing pneumonia. The recent consensus conference on VAP [11] concluded that risk factors vary, depending on the duration of exposure to intubation. For example, in a study [6] investigating pneumonia occurring within 48 h after intubation, antibiotic exposure had a protective effect (OR 0.29). In contrast, antibiotic exposure significantly increased the risk of VAP (OR 1.42) for episodes that developed later than 48 h. The study by Cook et al. [9] supports this observation. MORTALITY Survival in patients with VAP is determined primarily by the degree of severity of illness at the time of diagnosis [12]. In a recent cohort study [10], 842 patients with VAP (mean interval between intubation and VAP of 3.3 days) were matched with 2243 control subjects, and hospital mortality did not differ (30.5% vs. 30.4%). This does not rule out the possibility that in certain subgroups of patients, such as patients with VAP caused by Pseudomonas aeruginosa [13 15] or methicillin-resistant Staphylococcus aureus (MRSA) [16], mortality may have been extra attributable. Nevertheless, patients with VAP [10] had significantly longer durations of mechanical ventilation (10 extra days), ICU stay (6 extra days) and hospital stay (11 extra days). COSTS The average excess hospital charges for nosocomial pneumonia were estimated to be US$1255 per patient in 1982 in a study by Pinner et al. [17], and US$2863 per patient in 1985 in another study by eyt et al. [18]. The largest US study [10] performed to date estimated the cost of VAP per patient in 1999 to be more than US$4000. Recently [19], the attributable cost of VAP (after adjustment for underlying severity) was approximately US$ PATHOPHYSIOLOGY AND PREVENTION There are only four routes though which bacteria can reach the lower respiratory tract to cause VAP: contiguous spread, haematogenous spread, inhalation, and aspiration. Haematogenous or contiguous routes of invasion are very rare. Contamination of the ventilator circuits is universal and rarely has clinical implications. Therefore, the ventilator circuit change interval does not affect the incidence of VAP [20]. However, improper manipulation of the circuits may allow condensate from the warm humidified air that ventilates patients to precipitate, and aerosolisation of bacteria is possible. Aspiration is the main route by which bacteria invade the lower airways and cause VAP. The endotracheal tube holds the vocal cords open, facilitating aspiration. Most patients are sedated, or even paralysed, and thus cannot cough efficiently. The magnitude of aspiration of gastric content is decreased in patients in a semi-upright position, particularly when they are enterally fed [21,22]. Once aspirated, the secretions pool above the inflated endotracheal tube cuff. Maintenance of the upper airway by early tracheotomy [23] or effective drainage of subglottic secretions [24] significantly reduces the incidence of VAP. The pressure in the endotracheal tube cuff changes [25], deforming it and allowing the secretions to be transported around the inflated cuff by capillary action [24,25]. Cuff pressure should be routinely monitored and maintained at above 25 cm of water, but under 30 cm of water to prevent tracheal injury, which is essential to ensure that subglottic drainage is effective [26]. Failure to avoid cuff leak is associated with introduction of the organisms into the distal airspaces. The defence mechanisms attempt to eliminate them, and the outcome will depend on the nature, bacterial burden and virulence of the organisms, as well as on the biological status of the host. If the tube is left in the trachea for several days, an infected biofilm develops on the inner surface of the endotracheal tube [27]. Application of effective infection control measures, including hand washing and micro-

3 32 Clinical Microbiology and Infection, Volume 11 Supplement 5, 2005 biological surveillance, is important for prevention. Unfortunately, the rate of implementation of evidence-based preventive measures [28] for VAP is low, and the reasons for barriers to implementing programmes are varied [29,30]. Educating healthcare professionals and heightening their awareness is the key to success [31 33]. Indeed, it is vital that all healthcare professionals participate in these programmes, and that these programmes are customised to each ICU in order to ensure continuous improvement in the provision of care to critically ill intubated patients. Potential measures of control (Table 1) should focus on the patient, the microorganisms, and the device. AETIOLOGY A report from The American Thoracic Society [34] and a further report from France [35] described the distribution of causative organisms for VAP according to easily identifiable risk factors. These studies suggested that classifying patients according to prior duration of mechanical ventilation and prior exposure or non-exposure to antibiotics provided a rational basis for anticipating the Table 1. Evidence-based measures to prevent ventilatorasociated pneumonia (modified from Rello et al. [30], Ricart et al. [31] and Zack et al. [32]) Strategy (1) Protection of the patient Use of gowns and gloves Adequate nutritional support C Avoidance of gastric over-distension Postural changes Semi-recumbent positioning Limitation of stress-ulcer prophylaxis (2) Measures targeting microorganisms Hand washing Chlorhexidine oral rinse Formal infection control programme C Avoidance of unnecessary antibiotics C Selective digestive decontamination A Routine parenteral antibiotics in comatose patients (3) Interventions targeting the invasive devices Adequate pressure of endotracheal cuff C Removal of nasogastric endotracheal tubes C Humidification with head moisture A exchangers Drainage of condensate from C ventilator circuits Subglottic drainage A Oral intubation D Evidence degree pathogens. Moreover, in a study comparing four treatment sites [36], we concluded that the causes of VAP varied markedly across different institutions. This can be explained by differences in patients demographics, strategies for prophylaxis, methods of diagnosis and, particularly, local patterns of resistant organisms. A further report from Namias et al. [37] confirmed that decisions regarding initial antibiotic choices should consider local patterns of resistance. Table 2 summarises the distribution of organisms in some major studies [35,36,71] of VAP. Haemophilus influenzae, Streptococcus pneumoniae and methicillin-sensitive S. aureus (MSSA) should be considered in patients without antibiotic exposure. Compared to patients with VAP caused by MSSA, cases associated with MRSA are often older and significantly more likely to have previous lung disease and to have undergone steroid therapy and a longer period of mechanical ventilation. Nearly all MRSA cases were exposed to antibiotics [38]. acteraemia, shock and mortality are significantly higher in MRSA pneumonia. In a study on VAP [39], non-fermenting Gram-negative bacilli accounted for 25% of the pathogens isolated by protected specimen brush, but they caused up to 80% of deaths related to pneumonia. P. aeruginosa and MRSA are the leading pathogens associated with death from pneumonia. Candida spp. are very commonly isolated. However, except in neutropenic or transplant patients, yeasts are isolated from the respiratory tract in the apparent absence of disease [40 42]. Other pathogens such as anaerobes [43], Legionella [44], viruses [45] or Pneumocystis carinii are uncommon. CLINICAL FEATURES In the presence of clinical signs of sepsis (particularly fever and leukocytosis), the source of infection should be investigated. Pneumonia is the result of an invading organism overwhelming lung defences. A local inflammatory response follows, which is always manifested by purulent respiratory secretions. In the absence of purulent respiratory secretions, the diagnosis of VAP is unlikely [46]. However, the only way to differentiate tracheobronchitis from VAP is by the presence of a radiological opacity. Radiological diagnosis is therefore mandatory for diagnosis. Wunderink et al. [47] reported that no single radiographic sign had a diagnostic accuracy

4 Rello et al. Management of pneumonia in the ICU 33 Table 2 Microorganisms causing ventilator-associated pneumonia (adapted from American Thoracic Society [34], Trouillet et al. [35] and Rello and Diaz [70]) Ibrahim et al. [72] (n ¼ 420) Trouillet et al. [35] (n ¼ 245) Rello et al. [36] (n ¼ 301) Aerobic Gram-positive MRSA 81 (19.3%) 20 (8.2%) 10 (3.3%) MSSA 62 (14.7%) 32 (13.1%) 38 (12.6%) Streptococcus pneumoniae 6 (1.4%) 3 (1.2%) 25 (8.3%) Other streptococci NR 33 (13.5%) 10 (3.3%) Other NR 23 (19.4%) 24 (7.8%) Aerobic Gram-negative Pseudomonas aeruginosa 130 (30.9%) 39 (15.9%) 102 (33.9%) Acinetobacter baumannii 16 (3.8%) 22 (9.0%) 38 (12.6%) Klebsiella pneumoniae 25 (5.6%) 9 (3.7) 0 (0%) Stenotrophomonas maltophilia 38 (9.0%) 6 (2.4%) 8 (2.6%) Enterobacter spp. 43 (10.2%) 5 (2.0%) 44 (14.6%) Proteus spp. 9 (2.1%) 7 (2.4%) 0 (0%) Haemophilus influenzae 19 (4.5%) 15 (6.1%) 26 (8.6%) Serratia spp. 13 (3.1%) 4 (1.6%) 0 (0%) Escherichia coli 9 (2.2%) 8 (3.3%) NR Other 19 (4.5%) 13 (5.3%) 23 (7.6%) Anaerobic flora NR 6 (2.4%) NR Fungi 28 (6.6%) NR NR Virus 5 (3.1%) NR NR NR, not reported; MRSA, methicillin-resistant Stapylococcus aureus; MSSA, methicillin-resistant Staphylococcus aureus. above 68%. In patients with acute lung injury, this correlation was particularly poor. In addition, many other entities in intubated patients can mimic VAP, such as atelectasis, pulmonary oedema or thromboembolic disease [48,49]. The clinical pulmonary infection score (CPIS) was created to predict the pre-test probability of pneumonia [50]. It combines information concerning body temperature, volume and appearance of tracheal secretions, chest X-ray results, white blood cell count, oxygenation and tracheal aspirate culture. Serial measurements of CPIS [51] have been used to monitor clinical resolution. A persistent low score after 3 days of therapy in patients in whom pneumonia was unlikely, based on the CPIS, allowed a substantial reduction in antibiotic use [49]. Limitations of the CPIS score include the subjective (chest radiograph and character of secretions) and retrospective (culture of tracheal aspirate) nature of some variables, as well as the arbitrary nature of element scoring. Obviously, the value of the presence of tracheal secretions should be different from that assigned to the number of blood leukocytes or oxygenation changes. Pneumonia should be suspected in the presence of purulent respiratory secretions plus an abnormal chest radiograph. In a critically ill patient in this setting, empirical broad-spectrum agents should be administered immediately. Microbiological testing should be performed to rule out other sources, and to identify the causative pathogen. This would permit prompt modification of therapy if there is resistance, or de-escalation if the microorganisms are sensitive to several agents. [52] DIAGNOSIS Decisions regarding the initiation of empirical therapy can be improved if a cytospin is available in the laboratory and initial antibiotic choices are based on direct staining of respiratory samples. Direct stains, available within 1 h, can be done from protected specimen brush [43], bronchoalveolar lavage [53] or tracheal aspirates [54]. Mertens et al. [55] reported that fewer than 10% of neutrophils in bronchoscopic samples is uniformly associated with negative cultures and should be followed by a careful search for alternative diagnoses. Moreover, the cellular product of the sample can be used to evaluate its quality. The presence of more than 1% of epithelial cells in bronchoscopic samples suggests heavy oropharyngeal contamination, making the interpretation of cultures unreliable [56]. The level may rise to ten squamous epithelial cells per lowpower field (magnification, 100) for tracheal

5 34 Clinical Microbiology and Infection, Volume 11 Supplement 5, 2005 aspirates [54]. Morris et al. [54] reported that 85% of tracheal aspirate specimens should be eliminated from analysis because they contained more than ten squamous epithelial cells per low-power field. Thus, the bacterial burden should be interpreted with consideration of the quality of the sample, the specific clinical setting of the patient (days of intubation and presence of co-morbidities), and the potential interference of antibiotics in cultures [46,57]. Quantitative bronchoscopic samples are more accurate [58], but are time-consuming, labourintensive and expensive, and may not be practical for many laboratories [11,59]. Contraindications exist, and management of the ventilator setting should be by an expert, maintaining positive endexpiratory pressures in hypoxaemic patients, as detailed elsewhere [46]. If bronchoalveolar lavage is performed to guide modification of therapy in patients with poor resolution [60], the impact on outcome is minimal. In contrast [61], modification of the antimicrobial regimen, based on early diagnostic testing (i.e., within 12 h of VAP suspicion), has been associated with resolution of 63% of episodes. What we have learned in the past decade [57,59 62] is that avoiding delay in sampling and starting therapy quickly is more important than the type of quantitative technique used. RATIONAL MANAGEMENT OF HOSPITAL-ACQUIRED PNEUMONIA Septic shock and refractory hypoxaemia (often in a context of organ dysfunction) are the most frequent mechanisms of death. VAP can be facilitated by previous lung damage caused by over-distension as a result of using high tidal volumes during mechanical ventilation or by other non-infectious mechanisms [63]. Ventilator-induced lung injury may also disseminate local pulmonary infection [64] to the bloodstream, producing bacteraemia, systemic inflammatory responses and multiple organ dysfunction. Delay in administration of effective therapy for intubated patients with VAP is associated with increases in mortality [61 63,65,66], morbidity, and cost [67]. Optimising survival in patients with VAP, as well as costs, is based on prompt, adequate therapy [68,69]. The key questions to address in a specific patient with VAP are: (1) when to start antibiotics, (2) how microbiological tests determine antibiotic changes ( de-escalation ), (3) what dose and duration, (4) what microorganisms should be covered, and (5) which initial agent. The choice of the initial antibiotic should be based on avoiding agents previously used in these patients [70], the patient s co-morbidities [34,71], length of hospitalisation [35,72] and local sensitivities [36]. b-lactam b-lactamase inhibitors, second-generation cephalosporins and ertapenem are adequate as empirical monotherapy in patients not having received previous antibiotic therapy during the first week of hospitalisation. However, in the presence of severe sepsis or infections caused by P. aeruginosa or MRSA, or when these pathogens are suspected, initial narrow-spectrum antibiotic regimens should not be used because they increase the risk of death due to inadequate therapy if resistant pathogens are implicated. Table 3 summarises the points that determine the management of VAP in our institution [71]. Knowledge of the local microbial epidemiology and susceptibility patterns is crucial in the clinician s choice of antibiotics [36]. Heterogeneous usage of antibiotics removes selective pressure [73]. A heterogeneous pattern of prescription reduces the likelihood of resistance [73,74] compared with protocols that maintain a standard option over a long period of time. Most clinical trials, and some guidelines based on experts opinions, recommend a minimum course of 2 weeks of therapy for uncomplicated respiratory infections [34]. Shorter antibiotic regimens have been favoured by some authors to reduce costs, adverse events and the emergence of antibiotic-resistant pathogens [75]. Longer courses of antibiotics can increase costs and sideeffects, and select resistant phenotypes, and did not prevent recurrences [76]. We recommend a patient-based approach that has been recently reported elsewhere [71]. The antibiotic penetration into lung tissues is of vital importance in therapy. Septic ventilated patients have increased volumes of distribution that expose them to poor clinical resolution if standard doses are prescribed. This suggests that adequate therapy should no longer be defined on microbiological grounds alone [52]. The unacceptably high attributable mortality rate of patients with pneumonia caused by S. aureus treated with vancomycin [16,77,78], when compared with cloxacillin [16,77] or linezolid [78,79], illustrates this problem. This difference

6 Rello et al. Management of pneumonia in the ICU 35 Table 3. The Tarragona strategy (modified from Sandiumenge et al. [71]) 1. Antibiotic therapy should be started immediately 2. Antibiotic choice can be targeted, in some cases, on direct staining 3. The prescription should be modified in light of microbiological findings 4. Prolonging antibiotic treatment does not prevent recurrences 5. Patients with chronic obstructive pulmonary disease or 1 week of intubation should receive combination therapy, because of the risk of ventilatorassociated pneumonia caused by Pseudomonas aeruginosa 6. Methicillin-resistant Staphylococcus aureus is not expected in the absence of antibiotic exposure, while methicillin-sensitive Staphylococcus aureus should be strongly suspected in comatose patients 7. Therapy against yeast is not required, even in the presence of Candida spp. colonisation 8. Vancomycin administration for Gram-positive pneumonias is associated with a very poor outcome 9. The specific choice of agent should be based on the regimen to which each patient has been exposed previously 10. Guidelines should be regularly updated and customised to local patterns is probably due to the poor lung penetration of vancomycin, with epithelial lining fluid concentration being lower than 4 mg L in 36% of ventilated patients [80], and with a plasma to epithelial lining fluid drug penetration of 15%. Similarly, in hospitals with imipenem-resistant strains of Acinetobacter baumannii, the option of using colistin is questionable. ecause of the low virulence of A. baumannii and the better penetration of carbapenems to the lung, a regimen of imipenem plus rifampin in pneumonia caused by imipenem-resistant A. baumannii should be preferred [81]. If strains remain susceptible to other agents, monotherapy is adequate. Optimal therapy depends on maintaining a concentration above the MIC in lung tissue [71]. Opportunities for therapeutic improvement [82] include optimising dosing, and considering pharmacokinetics and pharmacodynamics and the area under the inhibitory curve (AUIC). The AUIC allows comparisons between drugs of different classes, regardless of their pharmacokinetic and pharmacodynamic responses. Strains of P. aeruginosa have different expressions of virulence, inducing different degrees of apoptosis and cytotoxicity [82]. Secretion of type III proteins has been associated with very poor outcomes (relapse or death) in patients with VAP [83]. This suggests that antibodies against the PcrV antigen might be incorporated into therapy (and prevention) of VAP caused by P. aeruginosa. Management of VAP in the year 2014 may conceivably be based on a combination of newer antibiotics [84], different principles of prescription [82] and immunotherapy [85]. ACKNOWLEDGEMENTS This work was supported, in part, by grants from Comissio Interdepartamental de Ciencia i Tecnologia (CIRIT) SGR and Distincio a la Recerca Universitaria (JR). REFERENCES 1. Haley RW, Hooton TM, Culver DH et al. Nosocomial infections in US hospitals, : estimated frequency by selected characteristics of patients. Am J Med 1981; 70: Rello J. Impact of nosocomial infections on outcome: myths and evidence. Infect Control Hosp Epidemiol 1999; 20: Rello J, Díaz E. Pneumonia in the intensive care unit. Crit Care Med 2003; 31: Richards MJ, Edwards JR, Culver DH et al. Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections Surveillance System. Crit Care Med 1999; 27: Kollef MH. Ventilator-associated pneumonia: a multivariate analysis. JAMA 1993; 270: Rello J, Diaz E, Roque M et al. Risk factors for developing pneumonia within 48 hours of intubation. Am J Respir Crit Care Med 1999; 159: National Nosocomial Infections (NNIS) system. Data summary from Jan 1992 June Am J Infect Control 2001; 29: Heyland DK, Cook DJ, Griffith L et al. The attributable mortality and mortality of ventilator-associated pneumonia in the critically ill study: the Canadian Clinical Trials Group. Am J Respir Crit Care Med 1999; 159: Cook DJ, Walter SD, Cook RJ et al. Incidence of and risk factors for ventilator-associated pneumonia in critically ill patients. Ann Intern Med 1988; 129: Rello J, Ollendorf DA, Oster G et al. Epidemiology and outcomes of ventilator-associated pneumonia in a large US database. CHEST 2002; 122: Hubmayr RD. Statement of the 4th International Consensus Conference in Critical care on ICU-acquired pneumonia Chicago, Illinois, May Intensive Care Med 2002; 28:

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