In 2005, the American Thoracic Society and Infectious Disease Society of America published an evidenced-based guideline for the management of hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and health care–associated pneumonia (HCAP).¹ This chapter provides basic information for the clinician and reviews guidelines for the management of HCAP. The key summary principles are summarized here.

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Summary

• HCAP is included in the spectrum of HAP and VAP, and patients with HCAP need therapy for multidrug resistant (MDR) pathogens.
• Early, appropriate, broad-spectrum antimicrobial therapy should be prescribed at adequate doses for all patients with suspected HCAP.
• A lower respiratory tract culture should be collected on all patients before antimicrobial therapy, but collection should not delay initiation of empirical therapy in critically ill patients.
• An empirical therapy regimen should not include antimicrobial agents that the patient has recently received.
• De-escalation of antibiotics (changing to narrow spectrum or oral therapy) should be considered once the results of cultures and the patient's clinical response are known.

Definitions

HAP is defined as pneumonia that occurs 48 hours or more after admission and that was not incubating at the time of admission. VAP refers to pneumonia that occurs more than 48 hours after endotracheal intubation. HCAP includes patients with pneumonia who are hospitalized in an acute care hospital for more than 2 days within 90 days of the pneumonia; those who resided in a long-term care facility (e.g., nursing home); those who received recent parenteral antimicrobial therapy, chemotherapy, or wound care within 30 days of pneumonia; or those who received treatment in a hospital or hemodialysis clinic. For practical purposes, most principles for HCAP, VAP, and HAP overlap.

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Epidemiology

HAP is the second most common nosocomial infection in the United States. There are 300,000 cases of HAP annually, and it carries an associated mortality rate of 30% to 70%.² It is difficult to determine the fraction of patients with HAP whose mortality is directly attributable to their pneumonia (the attributable mortality), but this rate is estimated to be between 27% and 50%.^2,3 This means that of the patients who develop HAP, it will be the proximate cause of death in 25% to 50% of them, and the remaining 50% to 75% will develop HAP but die from some other cause. HAP lengthens the hospital stay by 7 to 9 days and is associated with a higher cost of medical care.

General risk factors for developing HAP include age older than 70 years, serious comorbidities, malnutrition, impaired consciousness, prolonged hospitalization, and chronic obstructive pulmonary diseases.²

HAP is the most common infection occurring in patients requiring care in an intensive care unit (ICU) and accounts for almost 25% of all nosocomial infections in ICU patients, with incidence rates ranging from 6% up to 52%.³ This increased incidence is because patients located in an ICU often require mechanical ventilation, and mechanically ventilated patients are 6 to 21 times more likely to develop HAP than nonventilated patients. Mechanical ventilation is associated with high rates of HAP because the endotracheal tube bypasses upper respiratory tract defenses, allows for pooling of oropharyngeal secretions, prevents effective cough, and can be a nidus for infection.² The development of HAP in mechanically ventilated patients portends a poor prognosis, with a rate of mortality 2 to 10 times higher for this group than for mechanically ventilated patients without HAP.

The timing of HCAP is an important epidemiologic variable and risk factor for pathogens and outcomes in patients with VAP and HAP. Early-onset pneumonia (within 96 hours) usually is associated with a better prognosis and fewer MDR pathogens than late-onset (5 days or more) VAP and HAP.¹

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Pathogenesis

HAP, VAP, and HCAP are likely to occur when a sufficiently large number of organisms are delivered to the lower respiratory tract so that host defenses are overwhelmed (e.g., by aspiration or contaminated respiratory therapy equipment), when host defenses are impaired (e.g., by immunodeficiency or steroids), or if particularly virulent organisms are involved.² Gram-negative bacteria (GNB) account for 55% to 85% of HAP infections, and gram-positive cocci account for 20% to 30%.⁴ GNB rarely causes community-acquired pneumonia, but hospitalized patients are exposed to organisms that nonhospitalized patients are not exposed to, and many factors directly related to hospitalization make patients more likely to develop and less able to fight infection.

Microaspiration of contaminated oropharyngeal secretions seems to be the most important of these factors, because it is the most common cause of HAP.² Microaspiration is a common event, even in nonhospitalized patients, occurring in as many as 50% of normal sleeping subjects and 70% of patients subject to some degree of sedation or depressed consciousness. Microaspiration in a hospitalized patient is more serious and more likely to cause infection because the oropharyngeal secretions aspirated are likely to contain organisms that are not present under normal circumstances but that frequently cause HAP. The oropharynx of hospitalized patients becomes colonized by GNB in as many as 35% of moderately ill and 73% of critically ill patients, often within the first 4 days of admission. With the introduction of these new pathogenic organisms into the oropharynx, the previously benign event of microaspiration now becomes a mechanism whereby virulent organisms are introduced into the lower respiratory tract and cause pneumonia.

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Causes

HAP, VAP, and HCAP are caused by a spectrum of bacterial pathogens, may be polymicrobial and rarely due to viral and fungal pathogens (unless immunocompromised patients; e.g., bone marrow transplants). Common pathogens include aerobic gram-negative bacilli (e.g., Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli) as well as gram-positive organisms such as Staphylococcus aureus.

Rates of HAP caused by MDR pathogens have been increasing and affect empirical therapy. A discussion of the mechanisms of resistance for specific bacterial pathogens is beyond the scope of this chapter but includes the following:

• Methicillin-resistant S. aureus (MRSA)
• MDR Pseudomonas aeruginosa (with resistance to carbapenems, fluoroquinolones, and antipseudomonal penicillins and cephalosporinases)
• Extended-spectrum beta-lactamase (ESBL) producing Enterobacter, E. coli, and K. pneumoniae
• Acinetobacter species, Stenotrophomonas (Pseudomonas) maltophilia, and Burkholderia cepacia, all of which have increasing resistance to commonly used antimicrobials

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Summary

Risk Factors for Multidrug-Resistant Pathogens¹

• Antimicrobial therapy was initiated within the preceding 90 days.
• Onset of pneumonia occurred after 4 days of hospitalization.
• Known MDR pathogens are circulating in the community or hospital.
• Immunosuppressive disease is present or immunosuppressive therapy has been initiated.

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Diagnosis

Testing for and diagnosing HAP are difficult, because there are no reliable tools to determine whether the patient has pneumonia as the explanation for the clinical signs and symptoms seen at the bedside and no reliable method for determining the causative pathogen when pneumonia is present.⁶ The diagnosis is initially made on clinical grounds by the finding of a new infiltrate on chest radiograph, fever, purulent sputum, or other signs of clinical deterioration. Unfortunately, this clinical method was shown to be specific for HAP in only 27 of 84 patients in a series reported by Fagon and colleagues,⁷ because other conditions, such as congestive heart failure, pulmonary embolism, atelectasis, acute respiratory distress syndrome (ARDS), pulmonary hemorrhage, or drug reactions, may mimic pneumonia, particularly in critically ill patients.¹ Lack of specificity in the clinical diagnosis gives rise to the need for more reliable diagnostic tools so that fewer patients will be treated with antibiotics for noninfectious causes. Although there are many different testing modalities that can be used, all have their limitations and none is sufficiently sensitive and specific to be considered a gold standard test.³

Blood cultures have diagnostic and prognostic values but their reported sensitivity is only 8% to 20%, and their role is therefore limited. Similarly, examination of expectorated sputum is neither sensitive nor specific and should not be routinely used.¹ The most useful noninvasive test is the examination of tracheobronchial aspirates (TBAs). This method has a high degree of sensitivity, as demonstrated in a study in which the offending organism was recovered from tracheal secretions in 29 of 31 patients.⁴ The weakness of this test is its inability to differentiate between the organism responsible for causing the pneumonia and harmless colonizers. Because of this limitation, the use of TBA lies in its negative predictive value and its ability to exclude the presence of resistant organisms, thus narrowing antibiotic coverage.

Invasive bronchoscopic techniques are able to take samples directly from the lower respiratory tract without contamination from upper airway or oral secretions and would seem to provide an advance in identifying the responsible pathogen.⁸ Surprisingly, when bronchoscopic techniques such as bronchoalveolar lavage (BAL) or the use of protected specimen brushes (PSBs) have been compared with less invasive methods, they do not appear to differ significantly in terms of sensitivity, specificity or, more importantly, patient morbidity and mortality.⁹ There is currently a lack of consensus on the role of invasive diagnostic testing for HAP, and it is the subject of ongoing debate.

One study regarding this issue compared the results of bronchoscopically obtained PSBs with those of TBAs in 76 mechanically ventilated patients who were already receiving empirical antibiotic therapy.⁹ In this study, more patients who received bronchoscopy with PSB had a change in their antibiotic regimen, but there were no significant differences in length of stay, days requiring mechanical ventilation, or mortality between the two groups. This study concluded that outcome is “not influenced by techniques used for microbial investigation.”

Another study compared the use of invasive testing, such as PSBs and BAL, with the use of noninvasive TBAs in 413 patients.¹⁰ This study showed an initial decrease in mortality, antibiotic use, and organ dysfunction at 14 days in patients in whom invasive techniques were used, but at a 28-day analysis the difference in mortality could not be similarly demonstrated. These and other studies have led many clinicians to the conclusion that noninvasive and invasive tools achieve similar diagnostic performance and therefore the use of invasive techniques cannot be justified in every patient with HAP.⁸ Others argue that if invasive testing is done within the first 12 hours after diagnosis and before antibiotics are administered, the improvement in diagnostic yield may be sufficient to merit its use.³

A review of this issue by Ewig and Torres⁸ has stated that invasive and noninvasive techniques do not differ significantly, both are less sensitive than specific, and the false-negative rate for these tests ranges from 30% to 40% and the false-positive rate from 20% to 30%. The review also stated that invasive diagnostic testing should not be performed early in the course of HAP, and the best way to make adjustments to the empirical antibiotic regimen is by the use of TBAs rather than invasive techniques. Furthermore, they stated that because of the poor sensitivity associated with invasive methods, empirical coverage should not be stopped on the basis of negative diagnostic testing alone, and that the potential role for invasive diagnostic evaluation lies in cases of nonresponse to initial treatment.

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Treatment

After HAP is diagnosed, it is imperative that antimicrobial therapy begin promptly, because delays in the administration of antibiotics have been associated with worse outcomes.³ One study in support of this concept has reported a mortality rate of 30% in patients who receive early appropriate therapy compared with a rate of 91% in patients who do not.¹¹ The initial selection of an antimicrobial agent is almost always made on an empirical basis and is based on factors such as severity of infection, patient-specific risk factors, and total number of days in hospital before onset.

Pneumonia is defined as severe if there is need for admission to an ICU, radiographic evidence of rapid progression, need for mechanical ventilation or high levels of inspired oxygen, or evidence of sepsis. Regardless of severity, the initial empirical treatment regimens for HAP or VAP in patients with no known risk factors for MDR pathogens, and who have early-onset pneumonia (within 5 days of hospitalization) should include coverage for a group of core organisms that includes antibiotic-sensitive, aerobic, enteric, gram-negative bacilli (Enterobacter spp., E. coli, Klebsiella spp., Proteus spp., and Serratia marcescens) community pathogens such as Haemophilus influenzae and Streptococcus pneumoniae, as well as methicillin-sensitive S. aureus. Recommended antibiotics would include ceftriaxone or a quinolone (e.g., ciprofloxacin or levofloxacin) or ampicillin-sulbactam or eratpenem.¹ Although it is acceptable to use a fluoroquinolone in the empirical regimen of patients with penicillin allergies, one study evaluated the use of penicillin skin testing in these patients.¹² It was found that most patients with a history of penicillin allergy can safely be treated with penicillin antibiotics, so penicillin skin testing may be a means whereby the use of fluoroquinolones can be decreased.

Regardless of the severity of infection, the initial empirical treatment regimens for HAP or VAP in patients at risk for infection with MDR pathogens should be targeted with agents known to be effective against these organisms. This would include patients with late-onset disease (within 4 days of hospitalization), other risk factors (e.g., prior use of broad-spectrum antibiotics), or both. The potential pathogens include P. aeruginosa, K. pneumoniae (ESBL strains), Acinetobacter spp., and MRSA. Empirical combination antimicrobial therapy should include an antipseudomonal cephalosporin (e.g., ceftazidime), antipseudomonal carbapenem (e.g., imipenem), or beta-lactam-beta-lactamase inhibitor (e.g., piperacillin-tazobactam), plus an antipseudomonal fluoroquinolone (e.g., ciprofloxacin) or aminoglycoside (e.g. tobramycin) plus vancomycin or linezolid (for MRSA). If Legionella is suspected, then this combination should also have a macrolide (e.g., azithromycin) added if a fluoroquinolone that has Legionella activity is not already part of the regimen¹ (Table 1).

Duration of Treatment

There is no consensus regarding the duration of antibiotic treatment for all patients with HAP, although if the initial clinical suspicion was low, antibiotics may be safely discontinued after 72 hours if the clinical picture has not changed significantly.¹³ Recommendations from the American Thoracic Society have suggested that the duration of treatment should be guided by severity, time to clinical response, and the pathogenic organism¹; however, a panel of experts has suggested that “the main factor for deciding the duration of therapy should be the time to clinical response and not the pathogen involved”³ and that patients should be treated for at least 72 hours after a clinical response is achieved.

Clinical response to antimicrobial therapy is not likely in the first 48 to 72 hours, so the empirical antibiotic regimen should not be changed during this time unless as directed by the results of microbiologic investigation.¹ In patients who fail to respond after this initial period, recommendations are that antibiotic coverage should be broadened, noninfectious causes considered, and invasive diagnostic testing performed. Appropriate diagnostic testing may include bronchoscopy with PSBs and BAL, radiographic tests to evaluate for the possibility of pleural effusions or abscesses that limit response, and computed tomography (CT) scanning of the sinuses to evaluate for sinusitis, because this may be a cause of persistent symptoms. After excluding all other causes in the nonresponding patient, it may be advisable to perform open lung biopsy for diagnostic purposes, even though this technique has not been shown to improve outcomes.²

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Summary¹

Recommendations for Assessing Response to Treatment

• Modifications of empirical therapy should be based on results of microbiology testing in conjunction with clinical parameters.
• Clinical improvement of HCAP usually takes 2 to 3 days and therefore therapy should not be changed during this period unless there is a rapid clinical decline.
• Narrowing therapy to the most focused regimen possible on the basis of culture data (de-escalation of antimicrobials) should be considered for the responding patient.
• The nonresponding patient should be evaluated for possible MDR pathogens, extrapulmonary sites of infection, complications of pneumonia and its therapy, and mimics of pneumonia. Testing should be directed to whichever of these causes is likely after physical examination of the patient.

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Prevention

Prevention is important because even when appropriate diagnostic and therapeutic procedures are used, HAP is associated with a high rate of mortality. Prevention strategies should focus on general measures for infection control, measures directed at specific patient risk factors, and measures to limit the use of antibiotics in an attempt to decrease the prevalence of resistant organisms.

Although most clinicians think that strategies for prevention are important, it must be noted that few techniques have been shown in well-designed experimental or epidemiologic studies to be of definite value, so most specific recommendations for the prevention of HAP are made on the basis of expert opinion rather than hard data. The Centers for Disease Control and Prevention has published a set of 74 recommendations for preventing bacterial nosocomial pneumonia¹⁴; only 15 of these recommendations were “strongly supported by well-designed experimental or epidemiologic studies” and 14 of those 15 recommendations dealt with general issues such as surveillance, education, hand washing, sterilization, proper use of gloves, value of vaccination, and sanitation. The recommendation that prophylactic antibiotics not be routinely administered was the only specific recommendation supported by well-designed studies; all other specific recommendations, such as prevention of aspiration and prevention of colonization, were based on less-stringent evidence or on expert opinions.

General measures for infection control such as proper hand washing, use of gloves, and measures to reduce contamination from respiratory therapy equipment are important factors in preventing HAP. Although the benefits of these practices are universally recognized, they are often not performed, as evidenced by an observational study performed in an ICU setting where only 10% of health care workers washed their hands before having direct patient contact and only 32% washed their hands after patient contact.¹⁵ Compliance with these general measures has repeatedly been shown to correlate with favorable outcomes, and stricter adherence to these guidelines is needed.

Patient-specific measures should be considered and, if other circumstances allow, followed for every hospitalized patient. Efforts should be made to reduce immunosuppression, reduce sedation, avoid transportation of patients out of the ICU, and provide adequate nutrition, because these measures have been shown to reduce the incidence of HAP. It has been shown that pneumonia is more common in patients with sinusitis.² Because the presence of nasally placed tubes is associated with sinusitis, it is recommended that endotracheal or gastric tubes be placed orally if possible.

Another intervention with proven benefit for mechanically ventilated patients is the use of subglottic secretion drainage, a method whereby oropharyngeal secretions are continuously suctioned in an effort to prevent pooling and thus aspiration.¹ Finally, body positioning seems to have an impact on the development of HAP. This has been evidenced by a study¹⁶ that was stopped early after an interim analysis found a significant difference in the development of HAP between patients in a supine position and patients in a semirecumbent position, probably because of the protective effects of the semirecumbent position against aspiration of refluxed gastric contents.

Other techniques, such as administration of prophylactic antibiotics or nonabsorbable antibiotics for the purpose of gastrointestinal decontamination, have been attempted in the past, with varying degrees of reported success. More recent literature has suggested that these methods should not be used because they have not consistently been shown to influence mortality or length of stay, and the use of antibiotics in this manner may lead to the development of resistant organisms.³ On the other hand, the results regarding the role of histamine blockers in the development of HAP are conflicting, but their use should not be specifically avoided in patients for this reason.¹

The notion that antibiotics select out resistant or virulent organisms, or both, has been suggested in a study that found that in mechanically ventilated patients who had previously received antibiotics, 65% of pneumonias were caused by Acinetobacter or Pseudomonas, but in antibiotic-naïve patients, only 19% of infections were caused by these pathogens.¹⁷ In another study, 11 of 14 patients who had previously received ceftazidime developed HAP caused by resistant strains of Acinetobacter but only 11 of 29 control patients developed similar infections.¹⁵ These observations have resulted in efforts to decrease the use of antibiotics, which in turn decreases the incidence of antibiotic-resistant pathogens and potentially improves patient outcomes.^18,19

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Suggested Readings

• Drakulovic MB, Torres A, Bauer TT, et al: Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet. 1999, 354: 1851-1858.
• Fagon JY, Chastre J, Domart Y, et al: Nosocomial pneumonia in patients receiving continuous mechanical ventilation. Prospective analysis of 52 episodes with use of a protected specimen brush and quantitative culture techniques. Am Rev Respir Dis. 1989, 139: 877-884.
• Kollef MH. Current concepts: The prevention of ventilator-associated pneumonia. N Engl J Med. 1999, 340: 627-634.
• Niederman MS, Craven DE, Bonten MJ, et al: Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005, 171: 388-416.
• Ruiz M, Torres A, Ewig S, et al: Noninvasive versus invasive microbial investigation in ventilator-associated pneumonia: evaluation of outcome. Am J Respir Crit Care Med. 2000, 162: 119-125.
• Singh N, Rogers P, Atwood CW, et al: Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med. 2000, 162: 505-511.
• Weber DJ, Raasch R, Rutala WA. Nosocomial infections in the ICU: The growing importance of antibiotic-resistant pathogens. Chest. 1999, 115: 34S-41S.
• Yates RR. New intervention strategies for reducing antibiotic resistance. Chest. 1999, 115: 24S-27S.