NOSOCOMIAL PNEUMONIA

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CHAPTER 96 NOSOCOMIAL PNEUMONIA

D. Brandon Williams, Amritha Raghunathan, David A. Spain, Susan I. Brundage

The two broad classes of pneumonia are nosocomial and community-acquired pneumonia. Nosocomial pneumonia is often referred to as hospital-acquired pneumonia (HAP), defined as pneumonia occurring 48 hours or more after admission that was not incubating at the time of admission. Postoperative pneumonia is essentially HAP, except in a patient who has undergone a surgical procedure. Finally, ventilator-associated pneumonia (VAP) refers to pneumonia occurring 48 hours or more after initiating mechanical ventilation via endotracheal intubation or tracheostomy.

Our goals in this chapter are to review the incidence of nosocomial pneumonia in the trauma patient, risk factors contributing to pneumonia, proven prevention strategies, the specifics of diagnosis, appropriate management of pneumonia once diagnosed, and associated morbidity and mortality relevant to the trauma population such as the relationship between prophylactic antibiotics, tube thoracostomy, and pneumonia.

INCIDENCE/MORBIDITY AND MORTALITY

Nosocomial infections cause significant mortality and morbidity in the critical care setting. HAP is the most common infection in the intensive care unit (ICU), causing between 25% and 48% of all nosocomial infections. Pneumonia is the leading cause of death due to hospital-acquired infections, with an estimated associated mortality ranging from 20% to 50%. The majority of nosocomial pneumonia episodes, 80%–90%, are associated with mechanical ventilation. While VAP makes up 90% of all infections in intubated patients, the overall reported incidence of VAP varies, with rates between 6% and 52%. The incidence varies due to differences in the definition of VAP in studies as well as differences in patient populations. There is, for example, a lower incidence in respiratory and medical ICUs (4.2 and 7.4 cases per 1000 ventilator days, respectively) as compared to trauma, neurosurgical, and burn units (15–16.3 cases per 1000 ventilator days). Although there is approximately a 1% cumulative risk per day of mechanical ventilation, the risk is highest in the first 5 days (approximately 3% per day), and steadily decreases after that. A number of studies place nosocomial pneumonia’s risk ratio for death around 2.0. Developing pneumonia increases the overall hospital stay by approximately 9–11.5 days, and for critically ill patients, increases the ICU stay by 4–6 days. In addition to prolonging hospital and ICU stays, pneumonia increases hospital cost by requiring more antibiotics, chest radiographs, and days of mechanical ventilation, with all its associated care. The attributable cost of a single episode of HAP is estimated to be between $12,000 and $16,000.

RISK FACTORS AND PREVENTIVE MEASURES

Nonmodifiable versus Modifiable Risk Factors

While the greatest risk factor for VAP is the duration of mechanical ventilation, there are many other independent predictors, including modifiable and nonmodifiable risk factors (Table 1).

Table 1 Risk Factors for Ventilator-Associated Pneumonia

Nonmodifiable Factors	Modifiable Factors Affording Prevention Strategies
Age > 60 Male gender History of COPD Presence of significant comorbidity Steroid use Admitting diagnosis of burns Admitting diagnosis of trauma Head trauma and other central nervous system disease Emergency or field intubation Need for emergency surgery

Duration of mechanical ventilation (>3 days)

Thoracoabdominal surgery

Endotracheal intracuff pressure of <20 cm H₂O

Supine positioning

Antacids or histamine type-2 antagonists

Elevated gastric pH

Aspiration

Use of paralytic agents

Glasgow Coma Scale < 9

Septic shock

Hypoalbuminemia

No prophylactic antibiotics in first

48. hours of ICU stay

Patient transport out of ICU

Hemodialysis

Blood transfusions

Acute Physiology and Chronic Health

Evaluation (APACHE) II score

ICU, Intensive care unit.

These risk factors are directly related to the pathogenesis of VAP. As the lower respiratory tract is sterile under basal conditions, the introduction of pathogens into the lungs and the impairment of traditional host defenses are necessary to cause infection. There is growing evidence that aspiration of pathogens colonizing or contaminating the oropharynx or gastrointestinal tract results in lower respiratory tract infection. Colonization of the endotracheal tube itself also may lead to alveolar infection during suctioning or bronchoscopy. Other less frequent sources include bacteremia and hematogenous spread or inhalation of infected aerosols.

Mechanical Ventilation

Mechanical ventilation is the greatest risk factor for HAP and is associated with a 6- to 20-fold increase in the risk of lung infection. Intubation itself increases the risk of pneumonia due to the potential for direct inoculation of pathogens into the lungs during the procedure. Therefore, intubation should be avoided, with noninvasive positive-pressure ventilation being the preferred alternative to mechanical ventilation, when clinically feasible. A prospective survey of those who underwent mechanical ventilation versus noninvasive ventilation showed that even after adjusting for the severity of illness using the Simplified Acute Physiology Score (SAPS II), both the risk of VAP as well as the risk of nosocomial infections in general were reduced. Other invasive procedures such as tracheostomy, bronchoscopy, placement of a nasogastric (NG) tube, and chest tube thoracostomy also increase the risk. Thoracic trauma and chest operations lead to a disproportionately higher incidence of VAP, likely due to direct inoculation of pathogens, as well as infection due to chest tube placement.

In a trauma or surgical unit, the majority of patients are mechanically ventilated secondary to the need for surgery. However, all efforts to decrease sedation and wean the patient to extubation postoperatively should be made. The risk of reintubation and emergency intubation should be minimized, as these events are also associated with increased risk of VAP.

Subglottic secretions are also potential sources of infection. A recent meta-analysis showed that continuous aspiration of subglottic secretions resulted in a 50% decrease in incidence of VAP. This was particularly beneficial in those who were mechanically ventilated for longer than 72 hours. If mechanical ventilation is necessary, this technique should be utilized. Besides this, the ventilator circuit can also become contaminated due to patient secretions. Many prospective randomized trials have shown that the incidence of VAP is not associated with the frequency of ventilator circuit changes. However, care should be taken to frequently clean the circuit and prevent aspiration of accumulated secretions. The endotracheal tube cuff pressure should also be greater than 20 mm H₂O to prevent tracking of bacterial pathogens around the cuff and into the lower respiratory tract.

Impaired Host Defenses

Markers of impaired host defenses, such as increased age, the presence of lung disease and other comorbidities including sepsis, steroid use, and a history of multiple blood transfusions have been shown to be risk factors. Patients with these risk factors should be carefully monitored with all precautionary measures implemented to prevent pneumonia.

Oropharyngeal Colonization

While the oropharynx is not colonized by enteric Gram-negative bacteria under normal conditions, such colonization is present in 75% of the ICU population within the first 48 hours of admission. Studies monitoring oropharyngeal colonization in the ICU have further shown that colonization with specific pathogens like Acinetobacter baumannii results in increased risk for subsequent development of VAP.

Oropharyngeal colonization can be reduced by aggressive oral hygiene and the use of the oral antiseptic chlorhexidine. Oral inspections, tooth brushing and mouth swabs should all be utilized on a regular basis. Multiple randomized trials have shown a 60% decrease in VAP in postoperative patients with the use of chlorhexidine.

Aspiration

Due to the association between VAP and aspiration, factors involved in increased risk of aspiration such as continuous sedation, a low Glasgow Coma Scale, use of paralytic agents, and a supine position have all been shown to increase the risk of VAP. All efforts should be made to reduce the aspiration of gastric and oropharyngeal contents. One randomized trial was stopped ahead of schedule when it was apparent that the supine position results in increased aspiration and increased incidence of VAP compared to the semirecumbent position. Therefore, patients should be semirecumbent with the head of the bed raised to an angle of 30–45 degrees whenever possible. Continuous lateral rotation of ICU patients has also shown a protective effect and is another possibility. Transporting patients out of the ICU for procedures also leads to increased risk of VAP. This is potentially due to the fact that they are supine during transport. Thus, patients should be kept semirecumbent during transport whenever possible.

While it has been postulated that enteral nutrition would result in increased risk of VAP compared to parenteral nutrition due to aspiration, the evidence goes against that hypothesis, with VAP odds ratios of 2.65 and 3.27, respectively. As parenteral feeding is associated with many other risks like bacteremia as a complication of intravascular lines, and bacterial overgrowth and translocation, enteral feeding is preferred. As enteral feeding in the supine position maximizes risk, with a 50% incidence of VAP, feeding in the semirecumbent position is preferable. Other hypotheses include a benefit to smaller nasogastric tubes as well as a benefit to postpyloric or small intestine feeding. However, neither of those techniques has been proven to decrease the risk of VAP.

Gastrointestinal Tract Bacterial Overgrowth

Given their associated predisposition to bacterial overgrowth in the gastrointestinal tract, antacids and histamine type-2 antagonists are also associated with increased risk of VAP. There have been multiple trials comparing various stress ulcer prophylaxis agents. While there have been controversial results on the effect of sucralfate on VAP, the latest large randomized trial showed that while sucralfate resulted in a significantly lower rate of VAP compared to ranitidine and antacids, it is associated with a higher incidence of gastrointestinal bleeding. Therefore, sucralfate is recommended in all patients except those with risk factors for gastrointestinal bleeding.

Selective decontamination of the digestive tract (SDD) may be effective in reducing incidence of VAP. It attempts to reduce oropharyngeal and gastric colonization with aerobic Gram-negative bacilli and Candida species, without affecting anaerobic flora. Most regimens include a combination of an aminoglycoside, amphotericin B, or nystatin, and a nonabsorbable antibiotic like polymyxin. Systemic cefuroxime was also added in a few trials. Multiple randomized controlled trials have shown that SDD results in reduced incidence of VAP, decreased hospital mortality, and a decrease in antibiotic-resistant microorganism infections as well. However, these preventive effects were inversely related to study quality, and were much less pronounced in hospitals with high levels of antibiotic resistance. Therefore, SDD is not recommended for routine use, particularly for patients with risk factors for resistant pathogens.

It has been postulated that the intravenous antibiotic component of SDD is the main cause of improved survival, and current randomized trials are evaluating the effect of prophylactic IV antibiotics around the time of intubation. Intravenous cefuroxime reduced the incidence of early-onset hospital-acquired pneumonia in one recent trial. Intravenous antibiotics are currently not recommended for routine use, pending results from further trials.

Resistant Organisms

There has recently been an increase in the incidence of VAP caused by resistant organisms. Risk factors for infection with one of these pathogens include a recent history of antibiotic use, hospitalization of 5 days or more, admission from an allied health facility, immunosuppressive disease or therapy, presence of a severe, chronic comorbidity, and a high frequency of antibiotic resistance in that particular hospital or community. Another recent study also showed that aspiration, emergency intubation, and a Glasgow Coma Score of 9 or less are specific risk factors for early-onset VAP that is caused by resistant organisms.

Putting All Risk Factors Together

Croce et al. recently reported a post-trauma VAP probability calculation formula incorporating many of these risk factors. The probability of VAP (P_VAP) equals e^f(x)/(1 + e^f(x)), where f(x) = −3.08 – 1.56 ( mechanism of injury, penetrating = 1, blunt = 0) − 0.12 (Glasgow Coma Scale score) + 1.37 (spinal cord injury where yes = 1, no = 0) + 0.30 (chest abbreviated injury score) + 1.87 (emergency laparotomy where yes = 1, no = 0) + 0.67 (units of blood transfused in the resuscitation room) + 0.05 (Injury Severity Score) + 0.66 (intubation in either the field or the resuscitation room, where yes = 1, no = 0). Over 2 months, this formula was 95% accurate in predicting subsequent development of VAP.

General Prophylaxis

Maximizing hand hygiene protocols and barrier precautions is crucial in preventing the spread of nosocomial infections. Compliance with hand hygiene protocols has improved with the introduction of alcohol foams and gels. These products have improved efficacy and take substantially less time to use compared to thorough hand washing. Health care personnel should use these products before and after any contact with patients who are being mechanically ventilated. Gowns and gloves should also be used appropriately in any situation where contamination with respiratory secretions or other bodily fluids is possible.

Effectiveness of Preventive Measures

Preventive measures are very effective in preventing VAP. One institution showed that the incidence of VAP decreased by 58% after an educational session emphasizing positioning (head of bed elevated >30 degrees), appropriate use of sedation, routine oral hygiene, and management of respiratory devices. As VAP routinely results in increased hospital stays and therefore cost, this program was very cost-effective and the estimated savings were over $400,000.

DIAGNOSIS

Pneumonia is suspected when a patient develops new or progressive radiographic lung infiltrates (Figure 1), along with a clinical scenario of pulmonary infection (i.e., fever, leukocytosis, purulent sputum, respiratory distress, and a worsening of oxygenation) (Table 2). Of note, in patients diagnosed with acute respiratory distress syndrome (ARDS), the suspicion of pneumonia should be especially high. Several studies have noted a higher incidence of pneumonia in patients with ARDS. For example, one study showed a pneumonia rate of 55% in patients with ARDS, versus 28% in those without. Another study noted a 60% incidence of pneumonia in patients with severe ARDS (Pa_O2/FI_O2 ratio < 150 mm Hg).

Figure 1 Chest x-ray with right lower lobe consolidation.

Table 2 Centers for Disease Control and Prevention Criteria for Defining Hospital-Acquired Pneumonia

Radiology	Signs/Symptoms	Laboratory
Two or more serial chest radiographs with at least one of the following: New or progressive and persistent infiltrate Consolidation Cavitation Pneumatoceles, in infants <1 year old Note: In patients without underlying pulmonary or cardiac disease (e.g., respiratory distress syndrome, bron-chopulmonary dysplasia, pulmonary edema, or chronic obstructive pulmonary disease), one definitive chest radiograph is acceptable.

At least one of the following:

Fever (>38° C or >100.4° F) with no other recognized cause

Leukopenia (<4000 WBC/mm³) or leukocytosis (>12,000 WBC/mm³)

For adults >70 years old, altered mental status with no other recognized cause

and

At least one of the following:

New onset of purulent sputum, or change in character of sputum or increased respiratory secretions, or increased suctioning requirements

New onset or worsening cough, or dyspnea, or tachypnea

Rales or bronchial breath sounds

Worsening gas exchange (e.g., O₂ desaturations [e.g., PaO2/FiO2 < 240], increased oxygen requirements, or increased ventilation demand)

At least one of the following:

Positive growth in blood culture not related to another source of infection

Positive growth in culture of pleural fluid

Positive quantitative culture from minimally contaminated specimen (e.g., BAL or PSB)

≥5% BAL-obtained cells contain intracellular bacteria on direct microscopic exam (e.g., Gram stain)

Histopathologic exam shows at least one of the following evidences of pneumonia:

Abscess formation or foci of consolidation with intense PMN accumulation in bronchioles and alveoli

Positive quantitative culture of lung parenchyma

Evidence of lung parenchyma invasion by fungal hyphae or pseudohyphae

BAL, Bronchoalveolar lavage; PMN, polymorphonuclear leukocytes; PSB, protected specimen brush; WBC, white blood cells.

Diagnostic Strategies

However, ventilated ICU patients often have radiographic infiltrates, fever, and thick respiratory secretions in the absence of pneumonia. To assess the diagnostic efficacy of clinical criteria alone for VAP, one study reviewed 25 patients who died while on mechanical ventilation and used lung histology plus quantitative lung culture as the standard for pneumonia. The presence of radiographic chest infiltrates plus two of three clinical criteria (leukocytosis, purulent secretions, fever) had a sensitivity of 69% and a specificity of 75%. Thus, it is important to obtain sputum cultures to confirm the diagnosis of VAP; additionally, identifying the causative organism(s) aids in selecting appropriate antibiotics.

Looking at trauma patients in particular, the utility of obtaining a sputum culture was illustrated in a study of 43 patients undergoing mechanical ventilation and demonstrating symptoms of pneumonia, namely fever, leukocytosis, purulent sputum, and changing radiographic infiltrates. Of this group, 20 had positive cultures with greater than or equal to 10⁵ colony-forming units (CFU) per milliliter. Antibiotics were discontinued in the other 23 patients, and 65% showed improvement after stopping the antibiotics. Overall, there was no difference in mortality between the two groups.

Methods of Obtaining Sputum Cultures

Samples for sputum culture may be obtained noninvasively, via tracheal aspiration, or invasively with bronchoscopy and either bronchoalveolar lavage (BAL) or a protected specimen brush (PSB). Positive tracheal cultures may reflect simple tracheal colonization, and overestimate the rate of pneumonia. Invasive cultures are more accurate in diagnosing pneumonia. In one multicenter, randomized trial of 413 patients, those receiving invasive, bronchoscopic management had a lower mortality at day 14, but not at 28, and lower mean sepsis-related organ failure assessment scores on days 3 and 7. At 28 days, the invasive management group had significantly more antibiotic-free days (11 ± 6 vs. 7 ± 7). A multivariate analysis showed a significant difference in mortality (hazard ratio 1.54, 95% confidence interval 1.10–2.16). Both BAL and PSB have sensitivities and specificities greater than 80%. Studies have shown these two techniques yield similar results (Table 3).

Table 3 Quantitative Cultures and Microscopic Examination of Lower Respiratory Tract Secretions in Diagnosis of Ventilator-Associated Pneumonia

Most studies involving BAL have used 10⁴ or 10⁵ CFU/ml as the threshold for a positive culture. The presence of numerous squamous epithelial cells suggests upper pharyngeal contamination, and calls into question the utility of the specimen. The presence of intracellular organisms can be detected by Gram stain, and is particularly useful as it provides a rapid result with high predictive value (see Table 3).

However, if bronchoscopic sampling is not immediately available, nonbronchoscopic techniques can reliably obtain lower respiratory tract quantitative cultures. Blinded bronchial sampling, mini-BAL, and blinded protected-specimen brush involve blindly wedging a catheter into a distal bronchus and obtaining a sample. A review of several studies suggests that the sensitivities and specificities of these techniques are similar to those involving fiberoptic bronchoscopy.

Bronchial sampling techniques aside, when there is a high suspicion of pneumonia, or the patient is clinically unstable or septic, antibiotic therapy should be initiated promptly regardless of whether bacteria is detected from the distal respiratory tract.

Impact of Prior Antibiotic Use on Diagnosis

As one might expect, prior antibiotic therapy can impair the ability to obtain accurate culture results. The key factor appears to be the duration of antibiotics. Initiation of antibiotic therapy within the preceding 24 hours decreases the chances of obtaining a positive sputum culture, although this impact is less pronounced for BAL than with other methods. However, in patients receiving antibiotics for more than 72 hours, the sensitivity and specificity of BAL and PSB are essentially unaffected. Thus, these modalities are still just as useful for diagnosing pneumonias in those patients in the midst of a course of antibiotics for some other site of infection.

Value of Clinical Pulmonary Infection Score in Trauma Patients

Lastly, the clinical pulmonary infection score (CPIS) is an attempt to optimize a noninvasive diagnostic approach by pooling several clinical indicators of pneumonia (Table 4). A CPIS greater than 6 has been shown to be highly suggestive of pneumonia and correlates with a high concentration of bacteria from invasive cultures. The main criticisms of the CPIS are that all elements are weighted equally even though some are stronger predictors of pneumonia, and that some elements are necessarily subjective, such as the interpretation of chest x-rays. Furthermore, most of the components of the CPIS may be altered by the systemic effects of trauma, and therefore simply reflect the systemic inflammatory response syndrome (SIRS). A recent study of 113 trauma patients with suspected pneumonia found the average CPIS score to be 7.0 in those with VAP confirmed by BAL versus 6.9 in those with a negative BAL. In this study the sensitivity and specificity of using a CPIS greater than 6 to diagnose VAP were only 65% and 41%, respectively.

Table 4 Calculation of Clinical Pulmonary Infection Score

Variable	Finding	Points
Temperature (° C)	≥365 and ≤384	0
	≥385 and ≤389	1
	≥39 or ≤36	2
Blood leukocytes (n/mm³)	≥4,000 and ≤11,000	0
	>4,000 or <11,000	1
	Plus band forms ≥50%	Add 1
Tracheal secretions	Absent	0
	Nonpurulent secretions present	1
	Purulent secretions present	2
Oxygenation (PaO₂/FIO₂)	>240 or ARDS^a	0
Oxygenation (PaO₂/FIO₂)	≤240 and no ARDS	2
Pulmonary radiography	No infiltrate	0
	Diffuse (or patchy) infiltrate	1
	Localized infiltrate	2
Progression of pulmonary infiltrates	No radiographic progression	0
Progression of pulmonary infiltrates	Radiographic progression (after CHF and ARDS excluded)	2
Culture of tracheal aspirate	Pathogenic bacteria cultured in very low to low quantity or not at all	0
	Pathogenic bacteria cultured in moderate or high quantity	1
	Same pathogenic bacteria seen on Gram stain	Add 1

ARDS, Acute respiratory distress syndrome; CHF, congestive heart failure; FIO₂, fraction of inspired oxygen; P_aO₂, arterial oxygen tension; PAWP, pulmonary arterial wedge pressure.

a Defined as PaO₂/FIO2 ≥200 and PAWP ≥18 mm Hg, with acute bilateral infiltrates.

MANAGEMENT

Adequate Initial Antibiotics

Effective treatment for HAP depends on rapid institution of an appropriate initial antibiotic. At least three separate studies have shown mortality to almost double when the initial choice of antibiotics was inadequate. Another study looked at patients receiving appropriate initial antibiotics, but with a delay of more than 24 hours from the time of meeting diagnostic criteria for VAP. In this group, VAPattributable mortality was 39.4%, compared to 10.8% in those receiving antibiotics in a timely manner.

The first step in treating pneumonia is to determine whether the responsible organism is likely to demonstrate antibiotic resistance. Hospitalization for 5 days or more and recent antibiotic or health care exposure are common risk factors for developing multidrug-resistant (MDR) pneumonia (Table 5).

Table 5 Risk Factors for Multidrug-Resistant Pathogens Causing Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia

After determining the likelihood of antibiotic resistance, an appropriate initial therapy is selected. If the likelihood of antibiotic resistance is low, suitable initial choices include a third- or fourth-generation cephalosporin, a fluoroquinolone, an antipseudomonal penicillin with a beta-lactamase inhibitor, or a carbapenem (Table 6). Also, knowing hospital-specific or even ICU-specific patterns of antibiotic resistance can be particularly useful in guiding antibiotic choices.

Table 6 Initial Empiric Antibiotic Therapy for Hospital-Acquired Pneumonia or Ventilator-Associated Pneumonia in Patients with No Known Risk Factors for Multidrug-Resistant Pathogens

Potential Pathogens	Recommended Initial Antibiotics
Streptococcus pneumonia, Haemophilus influenzae, Methicillin-sensitive Staphy-lococcus aureus (MSSA) Enteric Gram-negative bacilli Escherichia coli Klebsiella pneumoniae Enterobacter sp. Proteus sp. Serratia marcescens

Ceftriaxone

Levofloxin or moxifloxin

Ampicillin/sulbactam

Ertapenem

If the patient has risk factors for MDR pneumonia, initial antibiotics should include double coverage for Gram-negatives and an agent for MRSA. The necessity of double antipseudomonal coverage is controversial. Evidence of in vitro synergy with combination therapy has been inconsistently demonstrated, and proof of clinical relevance is lacking. Also, prevention of emergent drug resistance during therapy has not been well demonstrated. However, one good reason to initiate double coverage is simply to increase the odds that at least one of the drugs will have activity against the suspected MDR organism. For MRSA coverage, it is important to remember that vancomycin has relatively poor lung penetration, and serum drug levels should be measured to ensure adequate dosage. Linezolid is another option, and two retrospective analyses comparing vancomycin to linezolid in treating MRSA nosocomial pneumonia showed improved survival and clinical cure rates with linezolid therapy (Table 7).

Table 7 Initial Empiric Therapy for Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia in Patients with Late-Onset Disease or Risk Factors for Multidrug-Resistant Pathogens

Potential Pathogens	Combination Antibiotic Therapy
Pathogens listed in Table 6 and MDR pathogens Pseudomonas aeruginosa Klebsiella pneumoniae (ESBL+)^a	Antipseudomonal cephalosporin (cefepime, ceftazidime) or Antipseudomonal carbepenem (imipenem or meropenem) or
Acinetobacter species^a	β-Lactam/β-lactamase inhibitor (piperacillin– tazobactam) plus Antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin) or Aminoglycoside (amikacin, gentamicin, or tobramycin) plus
Methicillin-resistant Staphylococcus aureus (MRSA) Legionella pneumophila^b	Linezolid or vancomycin