Hospital-acquired pneumonia (HAP) is the second

Guidelines and Critical Pathways for Severe Hospital-Acquired Pneumonia* Stanley Fiel, MD, FCCP Hospital-acquired pneumonia (HAP) is associated with high morbidity and mortality. Early, appropriate, and adequate empiric therapy can increase the chance of survival. In 1995, the American Thoracic Society provided guidelines for the initial treatment of immunocompetent HAP patients, which is one of the principal HAP management approaches available to physicians today. However, these guidelines have several important limitations, including a lack of recommendations for duration of therapy and no recognition of newer drugs such as cefepime, trovafloxacin, and meropenem. Furthermore, they fail to distinguish among similar compounds (ie, -lactam/ -lactamase inhibitor combinations) or to recommend specific antibiotics. The clinician using these guidelines needs to address local patterns of antimicrobial resistance, especially in ICUs. Effective computerized antibiotic management programs that incorporate information on local patterns of antimicrobial resistance can assist physicians in empiric therapy decision making, improve patient quality of care, and reduce medical costs. (CHEST 2001; 119:412S 418S) Key words: American Thoracic Society guidelines; antibiotic resistance; antibiotics; empiric therapy; hospital-acquired pneumonia; nosocomial pneumonia; patient quality of care Abbreviations: ATS American Thoracic Society; HAP hospital-acquired pneumonia; MRSA methicillin-resistant Staphylococcus aureus; MSSA methicillin-sensitive Staphylococcus aureus Hospital-acquired pneumonia (HAP) is the second most common nosocomial infection in the United States, but it has the highest morbidity and mortality. 1 Between one third and one half of all HAP patient deaths are directly attributable to the nosocomial infection, with mortality rates even higher if bacteremia or certain pathogens (eg, Pseudomonas aeruginosa or Acinetobacter) are involved. 1 Clinical studies have led to a consensus that empiric antibiotic therapy can reduce the HAP patient mortality rate and should be the preferred treatment strategy. 2 5 National guidelines for initial empiric treatment of HAP patients, such as those proposed by the American Thoracic Society (ATS) in 1995, are available to assist physicians in the management of their patients. 1 The ATS HAP management recommendations have provided helpful guidance since 1995, but the guidelines need updating. Furthermore, some gaps need to be addressed. For example, the original guidelines do not provide a suggested approach for incorporating information on local patterns of antibiotic resistance into the HAP management program of a given hospital. They do *From MCP Hahnemann School of Medicine, Philadelphia, PA. Correspondence to: Stanley Fiel, MD, FCCP, Professor of Medicine, MCP Hahnemann School of Medicine, 3300 Henry Ave, Philadelphia, PA 19129 not address the growing role of computers as the premiere vehicles for information dissemination, nor do they recognize how computer-assisted anti-infectives management programs can effectively assist clinicians in their decision making for HAP patients. 6,7 This article will review the 1995 ATS guidelines and key supporting clinical data for the initial empiric treatment of HAP patients, as well as some of the limitations of the ATS guidelines and the potential use of computers in patient care. Effective Therapy Reduces HAP Mortality Early, appropriate, and adequate antibiotic therapy has been found to reduce HAP patient mortality rates in clinical studies. A patient with a diagnosis of nosocomial pneumonia who receives appropriate antibiotic therapy is more than twice as likely to survive (Fig 1). 2 4 A more recent study 5 not only supports those data but further identifies the timing and adequacy of therapy as equally important factors. Patients with ventilator-associated pneumonia who receive early and adequate antibiotic therapy before completion of invasive diagnostic testing (bronchoscopy with BAL) have the lowest mortality rates, whether or not their HAP is subsequently confirmed by microbiological data (Fig 2). 5 How- 412S

Figure 1. Appropriate antibiotic therapy reduces HAP patient mortality rates. 2 4 ever, altering therapy after microbiological data become available has no effect on mortality rate. Patients who initially receive inadequate therapy that is changed in response to positive diagnostic test results have outcomes similar to those of patients who start and continue with inadequate therapy (Fig 2). 5 Since HAP diagnosis remains difficult and controversial and the timing of antibiotic therapy in relation to clinical recognition of the pneumonia is a major factor influencing mortality, initial empiric therapy is the best response to the challenge. 1,5,8,9 Review of ATS Guidelines In 1995, the ATS, following an extensive review of available information on HAP, published practical guidelines for the initial empiric treatment of HAP. 1 An HAP clinical management algorithm was developed using information on disease severity, the presence of risk factors for specific organisms, and time of onset of HAP ( 5 days after hospital admission). All these factors can influence the spectrum of likely HAP pathogens. 1 An overview of the Figure 2. Early and adequate antibiotic therapy reduces HAP patient mortality rates. 5 MID microbiological identification. ATS algorithm for HAP patient classification and treatment recommendations is presented in Figure 3. Patients who have mild-to-moderate HAP who are free of risk factors for specific pathogens, and patients with a diagnosis of early-onset severe HAP are presumed to be infected with one or more microorganisms of the core group (ATS 1 in Fig 3 and Table 1). This core group of pathogens includes the usual enteric Gram-negative bacilli suspects, as well as methicillin-sensitive Staphylococcus aureus (MSSA) and Streptococcus pneumoniae. 1 The ATS-recommended monotherapy for those HAP patients include second-generation cephalosporins, nonpseudomonal third-generation cephalosporins (cefotaxime or ceftriaxone), or a -lactam/ -lactamase inhibitor combination (ampicillin/sulbactam, ticarcillin/clavulanate, or piperacillin/tazobactam). In those patients allergic to penicillin, a fluoroquinolone (such as ciprofloxacin) may be employed if S pneumoniae has been excluded. Alternatively, aztreonam may be given as monotherapy or in combination with clindamycin. 1 The presence of specific risk factors (Table 2) in patients with mild-to-moderate HAP may signal the involvement of additional organisms such as Legionella, P aeruginosa, S aureus, or anaerobes in addition to the core pathogen(s) (ATS 2 in Fig 3 and Table 1). 1 These risk factors include patient-related conditions, infection control-related problems, and intervention-related alterations in host defenses or bacterial exposure. 1 The ATS-recommended therapy for this patient group is a combination of antiinfective agents directed toward the core group of pathogens and the specific risk factor-dependent organism. 1 However, in some situations, a -lactam/ -lactamase inhibitor combination may be sufficient to combat both the risk factor-associated organism as well as the core pathogen(s). 1 Although a core pathogen, S aureus is of special concern in HAP patients with diabetes, coma, head injury, renal failure, or recent influenza. 1 In those patients, the ATS guidelines suggest that additional treatment with vancomycin be considered until methicillinresistant S aureus (MRSA) is excluded. 1 The definition of severe HAP is essentially the same as that developed for severe community-acquired pneumonia (Table 3). 1,10 Patients with severe HAP generally require admission to an ICU. 1 Patients in the ICU for mechanical ventilation, or with severe sepsis or acute renal failure, also have increased risk of developing severe HAP. 1 If the onset of severe HAP is within 5 days of hospital admission, patients who do not present with additional pathogen-specific risk factors are likely to be infected with only the core organism(s) and should be treated accordingly (ATS 1 in Fig 3 and Table 1). 1 However, CHEST / 119 / 2/ FEBRUARY, 2001 SUPPLEMENT 413S

Figure 3. ATS algorithm for patient classification and treatment recommendations. Adapted from ATS 1995, with permission. 1 if severe HAP develops 5 days after hospitalization, several highly resistant Gram-negative organisms, such as P aeruginosa and Acinetobacter, are likely to be involved in addition to the core pathogen(s) (ATS 3 in Fig 3 and Table 1). 1 This group of additional pathogens should also be suspected in patients with severe HAP who present with risk factors (Table 2), regardless of time of onset. 1 For patients classified under ATS 3, the group strongly recommends the addition of antimicrobial agent(s) effective against P aeruginosa and Acinetobacter to a core antibiotic. 1 Antibiotics effective against such pathogens include the antipseudomonal penicillins, either singly or in combination with a -lactamase inhibitor, some third-generation cephalosporins, aztreonam, imipenem, aminoglycosides, and fluoroquinolones. 1 Despite these guidelines, if resistance to the quinolones has been a problem in a particular hospital, a combination of a -lactam/ lactamase inhibitor with an aminoglycoside instead of a fluoroquinolone may be preferred, even in patients with renal failure. Although the guidelines suggest initial treatment with a combination of antiinfectives, some patients may be able to complete Table 1 ATS HAP Organism Classification and Recommended Antibiotic Treatment Program* ATS Classification Organisms Antibiotics 1 Enteric Gram-negative bacilli: Enterobacter (nonpseudomonal) E coli Klebsiella Proteus Serratia marcescens Haemophilus influenzae MSSA S pneumoniae Third-generation nonpseudomonal cephalosporins (cefotaxime, ceftriaxone) if Enterobacter suspected, use in combination with another agent OR -Lactam/ -lactamase inhibitor combination (ampicillin/sulbactam, ticarcillin/clavulanate, piperacillin/tazobactam) If allergic to penicillin: Fluoroquinolone (ciprofloxacin) or clindamycin plus aztreonam 2 ATS 1 core organisms anaerobes ATS 1 core antibiotic regimen plus -lactam/ -lactamase inhibitor combination or clindamycin S aureus Vancomycin (until MRSA excluded) Legionella Macrolide (erythromycin) with or without rifampin P aeruginosa Treat as per ATS 3 3 ATS 1 core organisms Acinetobacter P aeruginosa Consider MRSA *Adapted from ATS 1995. 1 Listed are the core organisms and antibiotic regimens. Aminoglycoside or ciprofloxacin plus one of the following: Antipseudomonal penicillin (piperacillin, ticarcillin) Antipseudomonal -lactam/ -lactamase inhibitor combination (piperacillin/tazobactam, ticarcillin/clavulanate) Aztreonam Imipenem Vancomycin 414S

Table 2 Risk Factors for Specific Pathogens (Noncore Pathogens) in HAP* Risk Factors Mild-to-moderate HAP (ATS 2) Witnessed aspiration, recent abdominal surgery 17,18 Coma, 19 head trauma, recent influenza, history of IV drug use, diabetes mellitus, renal failure High-dose steroids 20 Prolonged ICU stay, steroids, antibiotics, structural lung disease 21,22 Severe HAP (ATS 3) Antibiotics before onset of pneumonia plus mechanical ventilation 21,23 Antibiotics before onset of pneumonia plus mechanical ventilation; corticosteroid therapy, malnutrition, structural lung disease (bronchiectasis, cystic fibrosis), prolonged hospitalization 22 Antibiotics before onset of pneumonia; prolonged mechanical ventilation 24 *From ATS 1995. 1 Development of severe HAP after 4 days of hospitalization is a risk factor for all the noncore pathogens shown. Pathogens Anaerobes S aureus Legionella P aeruginosa Acinetobacter P aeruginosa MRSA therapy with only one antimicrobial agent, especially if P aeruginosa and other resistant pathogens are not present and the patient is improving clinically. 1 Limitations of the ATS Guidelines The ATS guidelines for initial treatment of immunocompetent HAP patients, although thoroughly considered, have several important limitations. Controversy persists over the reliability of methods (eg, clinical examination vs invasive microbiological techniques) used to diagnose pneumonia and the role of invasive diagnostic procedures to quantitate microbial load in patients with clinical HAP. 1 Questions regarding who should be tested and how frequently, the use of specific bacterial counts for defining pneumonia, the possibility of false-negative results due to previous antibiotic therapy, and the reliability of results from the technically demanding invasive diagnostic procedure are still being debated. 1 The importance of invasive diagnostic procedures in the management of HAP patients is questionable, since clinical studies demonstrating the value of invasive diagnostic testing in place of clinical diagnosis are Table 3 ATS Definition of Severe HAP* Admission to the ICU Respiratory failure, defined as the need for mechanical ventilation or the need for 35% oxygen to maintain an arterial oxygen saturation 90% Rapid radiographic progression, multilobar pneumonia, or cavitation of a lung infiltrate Evidence of severe sepsis with hypotension and/or end-organ dysfunction: Shock (systolic BP 90 mm Hg, or diastolic BP 60 mm Hg) Requirement for vasopressors for 4h Urine output 20 ml/h or total urine output 80 ml in 4 h (unless another explanation is available) Acute renal failure requiring dialysis *Adapted from ATS 1995, 1 with permission. lacking and because of the proven benefit of initiating empiric therapy before the causative agent(s) are cultured and identified. 1 The optimal length of antibiotic therapy for HAP needs to be addressed in clinical studies. 1 Except for certain situations (eg, the presence of multilobar involvement, malnutrition, severe debilitation, cavitation, a necrotizing Gram-negative bacillus pneumonia, or an MSSA or Haemophilus influenzae pneumonia), the ATS guidelines provide no recommendation on the duration of therapy. 1 The ATS guidelines of 1995 have several limitations in the discussion of antibiotics and recommended therapies. Since the guidelines were published in 1995 without update, they do not include newer therapies (eg, cefepime, meropenem, and trovafloxacin) that may be effective and/or associated with less resistance. For those antibiotic families containing multiple compounds (eg, cephalosporins, -lactam/ -lactamase inhibitor combinations), the ATS made no recommendations or attempts to distinguish among the available options, either within any particular antibiotic group or between groups, unless supported by clinical study data. 1 The ATS guidelines were also based on the expected antimicrobial spectra of commonly employed antibiotics, while acknowledging that few clinical trials have evaluated the efficacy or superiority of their suggested protocols. 1 However, important data from recent studies should be evaluated and the information incorporated into the guidelines. The heavy use of third-generation cephalosporins and aztreonam is associated with the emergence of extended-spectrum -lactamases, resulting in significant transferable drug-resistance problems. 11 In contrast, drugs like piperacillin/tazobactam, which may be substituted for a cephalosporin in the treatment of patients with moderate-to-severe HAP, are not associated with extended-spectrum -lactamase emergence. 11 Piperacillin/tazobactam has emerged CHEST / 119 / 2/ FEBRUARY, 2001 SUPPLEMENT 415S

as an important broad-spectrum antibiotic combination that is active against Gram-positive aerobes, including enterococci, Gram-negative aerobes, and anaerobes and may offer the convenience of monotherapy in certain situations. This -lactam/ -lactamase inhibitor combination drug coupled with tobramycin has been shown in clinical trials to have greater efficacy and a more favorable bacteriologic response for both unimicrobial and polymicrobial pneumonias than ceftazidime plus tobramycin. 12 Those favorable responses translated into significantly less mortality in the piperacillin/tazobactam therapy group than in the ceftazidime group. Studies since the 1980s have well documented the increase in antibiotic resistance and nosocomial outbreaks worldwide. 13 16 In hospitals in the United States, Canada, and Latin America, the most common bacterial pathogens associated with bloodstream infection were S aureus, Escherichia coli, and coagulase-negative staphylococci; the most frequent Gram-negative organisms were E coli, Klebsiella species, and P aeruginosa (Table 4). 16 Of special concern are antibiotic-resistant microorganisms encountered in the ICU. A recent analysis of antibiotic susceptibility among aerobic Gram-negative bacilli in European ICUs indicated significant resistance to multiple compounds and the need for more effective strategies to control the selection and spread of resistant organisms. 15 These findings highlight the need for a faster means of incorporating information on local patterns of resistance and patterns in particular hospital services (eg, the ICU or burn unit) into the global framework of the guidelines. This step is vital in order to maintain effective antimicrobial therapies and is of special concern for HAP and ICU patients because of their high proportion of mortalities. Computer-Assisted Anti-infectives Management Programs Many hospitals have established their own surveillance programs to monitor pathogen distribution and resistance patterns. Computer-assisted antibiotic management programs can facilitate the dissemination of such information to physicians for immediate use in therapy decision making. One community teaching hospital employed a computer-assisted antibiotic management program with guidelines devised by local clinicians for a 7-year period and found antibiotic use had improved while costs were reduced, and adverse drug reactions were minimized while the emergence of antibiotic-resistant pathogens stabilized. 6 In a follow-up study, in which a 2-year preintervention period was compared with a 1-year intervention term, the use of a computerized anti-infectives management program was found to improve the quality of patient care and reduce costs. 7 The study Table 4 Frequency of Occurrence of Bacterial Pathogens Associated With Bloodstream Infection in Medical Centers in the United States, Canada, and Latin America* Organisms Total (n 9,519) United States (n 6,150) Canada (n 1,727) Latin America (n 1,642) S aureus 2,151 (22.6) 1,467 (23.9) 348 (20.2) 336 (20.5) E coli 1,751 (18.4) 1,141 (18.6) 329 (19.1) 281 (12.1) Coagulase-negative 1,256 (13.2) 778 (12.7) 227 (13.1) 250 (15.2) staphylococci Enterococcus species 794 (8.3) 589 (9.6) 157 (9.1) 48 (2.9) Klebsiella species 765 (8.0) 473 (7.7) 123 (7.1) 169 (10.3) S pneumoniae 475 (5.0) 341 (5.5) 102 (5.9) 32 (1.9) P aeruginosa 451 (4.7) 276 (4.5) 83 (4.8) 92 (5.6) Enterobacter species 399 (4.2) 232 (3.8) 71 (4.1) 96 (4.8) -Hemolytic streptococci 307 (3.2) 225 (3.7) 57 (3.3) 25 (1.5) Acinetobacter species 206 (2.2) 100 (1.6) 19 (1.1) 87 (5.3) Viridans group streptococci 154 (1.6) 68 (1.1) 71 (4.1) 15 (0.9) Serratia species 136 (1.4) 68 (1.1) 32 (1.9) 36 (2.2) Proteus mirabilis 122 (1.3) 88 (1.4) 18 (1.0) 16 (1.0) Salmonella species 93 (1.0) 33 (0.5) 10 (0.6) 50 (3.0) Citrobacter species 76 (0.8) 50 (0.8) 16 (0.9) 10 (0.6) Stenotrophomonas maltophilia 69 (0.7) 43 (0.7) 11 (0.6) 15 (0.9) Pantoea agglomerans 44 (0.5) 25 (0.4) 8 (0.5) 11 (0.7) Haemophilus species 27 (0.3) 20 (0.3) 7 (0.4) 0 (0.0) Morganella morganii 26 (0.3) 16 (0.2) 6 (0.3) 4 (0.2) Corynebacterium species 20 (0.2) 14 (0.2) 3 (0.2) 3 (0.1) *Data are presented as No. of isolates (% of total). Adapted from Diekema et al 16 with permission. 416S

populations for both periods were similar, with 10% of patients having respiratory tract infections. Although the distribution of pathogens did not vary between periods, there were increases in bacteremias and infections by P aeruginosa and enterococcal species and decreases in infections caused by S aureus and E coli during the intervention period. 7 Other outcomes showing significant changes during the intervention period included the following: percentage of patients receiving anti-infective agents (increased), number of adverse drug reactions (decreased), number of susceptibility-mismatch alerts (decreased), number of drug-allergy alerts (decreased), number of excessive-drug-dosage alerts (decreased), and average number of days receiving an excessive anti-infective dosage (decreased). 7 During the intervention period, patients received an average of 4.7 fewer doses of anti-infective agents (p 0.042), had an average decrease of $81 in the cost of anti-infective agents (p 0.079), and received an excessive dose of an anti-infective for an average of 2.9 fewer days. 7 Implementation of the program also had a significant impact on factors affecting cost. A comparison of means adjusted for age, sex, computer severity index score on admission to unit, medical service, and mortality indicated reductions in the number of doses of anti-infective agents, the cost of the anti-infective agents, total length of stay, and total cost of hospitalization. 7 Physicians were permitted to override the management program s suggestions, and all those who overrode had valid reasons for doing so. However, when suggestions were overridden, cost savings were negated, sometimes to the point to which preintervention-period costs were less. 7 Summary Despite our improved understanding of the pathogenesis, diagnosis, therapy, and prevention of HAP, it remains the leading cause of mortality stemming from nosocomial infections. Early, adequate, and appropriate empiric antibiotic therapy can save the lives of more than half of all HAP patients. The 1995 ATS guidelines for initial empiric treatment of HAP are perhaps the best currently available. However, they are limited in several important ways, most notably in their failure to address the need to incorporate information on local patterns of antibiotic resistance. Computer-assisted antibiotic management programs can effectively aid clinicians in their decision-making processes, resulting in improved patient quality of care and reduced medical costs. Appendix Dr. Stanley Fiel: In a recent JAMA article written by Hanberger et al, 15 antibiotic susceptibility among aerobic Gram-negative bacilli was looked at in ICUs in five European countries. Resistance was either relatively high or higher than I would have expected in this particular group of European countries. What are some of the reasons for this observation that you may know about through your surveillance? Dr. Ronald Jones: These data come out of the Merck ICU program, the same as the one in the United States. It is composed of groups of 10 to 20 to 30 laboratories in individual nations. The database is actually old; 1993 to 1995 data points are in the article. Those rates look fairly comparable with what was coming out of national programs during that same period of time. I think those rates are relatively accurate, and they were using a reliable surveillance method that focused only on Gram-negatives during that surveillance. There are a lot of differences in antibiotic use among those nations. I think it is more controlled in Sweden. References 1 American Thoracic Society. Hospital-acquired pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy, and preventative strategies. Am J Respir Crit Care Med 1995; 153:1711 1725 2 Moore RD, Smith CR, Lietman PS. Association of aminoglycoside plasma levels with therapeutic outcome in Gramnegative pneumonia. Am J Med 1984; 77:657 662 3 Celis R, Torres A, Gatell JM, et al. Nosocomial pneumonia: a multivariate analysis of risk and prognosis. Chest 1988; 93:318 324 4 Torres A, Aznar R, Gatell JM, et al. Incidence, risk, and prognosis factors of nosocomial pneumonia in mechanically ventilated patients. Am Rev Respir Dis 1990; 142:523 528 5 Luna CM, Vujacich P, Niederman MS, et al. Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia. Chest 1997; 111:676 685 6 Pestotnik SL, Classen DC, Evans RS, et al. Implementing antibiotic practice guidelines through computer-assisted decision support: clinical and financial outcomes. Ann Intern Med 1996; 124:884 890 7 Evans RS, Pestotnik SL, Classen DC, et al. A computerassisted management program for antibiotics and other antiinfective agents. N Engl J Med 1998; 338:232 238 8 Fagon J-Y, Chastre J, Hance AJ, et al. Detection of nosocomial lung infection in ventilated patients: use of a protected specimen brush and quantitative culture techniques in 147 patients. Am Rev Respir Dis 1988; 138:110 116 9 Papazian L, Thomas P, Garbe L, et al. Bronchoscopic or blind sampling techniques for the diagnosis of ventilator-associated pneumonia. Am J Respir Crit Care Med 1995; 152:1982 1991 10 American Thoracic Society. Guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy. Am Rev Respir Dis 1993; 148:1418 1426 11 Gold HS, Moellering RC Jr. Antimicrobial-drug resistance. N Engl J Med 1996; 335:1445 1453 CHEST / 119 / 2/ FEBRUARY, 2001 SUPPLEMENT 417S

12 Joshi M, Bernstein J, Solomkin J, et al. Piperacillin/tazobactam plus tobramycin versus ceftazidime plus tobramycin for the treatment of patients with nosocomial lower respiratory tract infection: Piperacillin/tazobactam Nosocomial Pneumonia Study Group. J Antimicrob Chemother 1999; 43:389 397 13 Zervos MJ, Terpenning MS, Schaberg DR, et al. High-level aminoglycoside-resistant enterococci. Arch Intern Med 1987; 147:1591 1594 14 Wiener J, Quinn JP, Bradford PA, et al. Multiple antibioticresistant Klebsiella and Escherichia coli in nursing homes. JAMA 1999; 281:517 523 15 Hanberger H, Garcia-Rodriguez J-A, Gobernado M, et al. Antibiotic susceptibility among aerobic Gram-negative bacilli in intensive care units in 5 European countries. JAMA 1999; 281:67 71 16 Diekema DJ, Pfaller MA, Jones RN, et al. Survey of bloodstream infections due to Gram-negative bacilli: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, and Latin America for the SENTRY Antimicrobial Surveillance Program, 1997. Clin Infect Dis 1999; 29:595 607 17 Bartlett JG, O Keefe P, Tally FP, et al. Bacteriology of hospital-acquired pneumonia. Arch Intern Med 1986; 146: 868 871 18 Mier L, Dreyfuss D, Darchy B, et al. Is penicillin G an adequate initial treatment for aspiration pneumonia? A prospective evaluation using a protected specimen brush and quantitative cultures. Intensive Care Med 1993; 19:279 284 19 Rello J, Quintana E, Ausina V, et al. Risk factors for Staphylococcus aureus nosocomial pneumonia in critically ill patients. Am Rev Respir Dis 1990; 142:1320 1324 20 Carratala J, Gudiol F, Pallares R, et al. Risk factors for nosocomial Legionella pneumophila pneumonia. Am J Respir Crit Care Med 1994; 149:625 629 21 Rello J, Ausina V, Ricart M, et al. Impact of previous antimicrobial therapy on the etiology and outcome of ventilator-associated pneumonia. Chest 1993; 104:1230 1235 22 Niederman MS. Gram-negative colonization of the respiratory tract: pathogenesis and clinical consequences. Semin Respir Infect 1990; 5:173 184 23 Fagon J-Y, Chastre J, Domart Y, et al. Nosocomial pneumonia in patients receiving continuous mechanical ventilation. Am Rev Respir Dis 1989; 139:877 884 24 Rello J, Torres A, Ricart M, et al. Ventilator-associated pneumonia by Staphylococcus aureus: comparison of methicillin-resistant and methicillin-sensitive episodes. Am J Respir Crit Care Med 1994; 150:1545 1549 418S