Pneumonia is an infection of the pulmonary parenchyma. Despite being the cause of significant morbidity and mortality, pneumonia is often misdiagnosed, mistreated, and underestimated. In the past, pneumonia was typically classified as community-acquired (CAP), hospital-acquired (HAP), or ventilator-associated (VAP). Over the past two decades, however, some persons presenting with onset of pneumonia as outpatients have been found to be infected with the multidrug-resistant (MDR) pathogens previously associated with HAP. Factors responsible for this phenomenon include the development and widespread use of potent oral antibiotics, earlier transfer of patients out of acute-care hospitals to their homes or various lower-acuity facilities, increased use of outpatient IV antibiotic therapy, general aging of the population, and more extensive immunomodulatory therapies. The potential involvement of these MDR pathogens has led to a designation for a new category of pneumonia—health care–associated pneumonia (HCAP)—that is distinct from CAP. Conditions associated with HCAP and the likely pathogens are listed in Table 153-1.
Although the new classification system has been helpful in designing empirical antibiotic strategies, it is not without its disadvantages. Not all MDR pathogens are associated with all risk factors (Table 153-1). Moreover, HCAP is a distillation of multiple risk factors, and each patient must be considered individually. For example, the risk of infection with MDR pathogens for a nursing home resident who has dementia but can independently dress, ambulate, and eat is quite different from the risk for a patient who is in a chronic vegetative state with a tracheostomy and a percutaneous feeding tube in place. In addition, risk factors for MDR infection do not preclude the development of pneumonia caused by the usual CAP pathogens.
TABLE 153-1Clinical Conditions Associated with and Likely Pathogens in Health Care–Associated Pneumonia ||Download (.pdf) TABLE 153-1Clinical Conditions Associated with and Likely Pathogens in Health Care–Associated Pneumonia
| ||Pathogen |
|Condition ||MRSA ||Pseudomonas aeruginosa ||Acinetobacter spp. ||MDR Enterobacteriaceae |
|Hospitalization for ≥48 h ||√ ||√ ||√ ||√ |
|Hospitalization for ≥2 days in prior 3 months ||√ ||√ ||√ ||√ |
|Nursing home or extended-care-facility residence ||√ ||√ ||√ ||√ |
|Antibiotic therapy in preceding 3 months || ||√ || ||√ |
|Chronic dialysis ||√ || || || |
|Home infusion therapy ||√ || || || |
|Home wound care ||√ || || || |
|Family member with MDR infection ||√ || || ||√ |
This chapter deals with pneumonia in patients who are not considered to be immunocompromised. Pneumonia in severely immunocompromised patients, some of whom overlap with the groups of patients considered in this chapter, warrants separate discussion (see Chaps. 104, 169, and 226).
Pneumonia results from the proliferation of microbial pathogens at the alveolar level and the host’s response to those pathogens. Microorganisms gain access to the lower respiratory tract in several ways. The most common is by aspiration from the oropharynx. Small-volume aspiration occurs frequently during sleep (especially in the elderly) and in patients with decreased levels of consciousness. Many pathogens are inhaled as contaminated droplets. Rarely, pneumonia occurs via hematogenous spread (e.g., from tricuspid endocarditis) or by contiguous extension from an infected pleural or mediastinal space.
Mechanical factors are critically important in host defense. The hairs and turbinates of the nares capture larger inhaled particles before they reach the lower respiratory tract. The branching architecture of the tracheobronchial tree traps microbes on the airway lining, where mucociliary clearance and local antibacterial factors either clear or kill the potential pathogen. The gag reflex and the cough mechanism offer critical protection from aspiration. In addition, the normal flora adhering to mucosal cells of the oropharynx, whose components are remarkably constant, prevents pathogenic bacteria from binding and thereby decreases the risk of pneumonia caused by these more virulent bacteria.
When these barriers are overcome or when microorganisms are small enough to be inhaled to the alveolar level, resident alveolar macrophages are extremely efficient at clearing and killing pathogens. Macrophages are assisted by proteins that are produced by the alveolar epithelial cells (e.g., surfactant proteins A and D) and that have intrinsic opsonizing properties or antibacterial or antiviral activity. Once engulfed by the macrophage, the pathogens—even if they are not killed—are eliminated via either the mucociliary elevator or the lymphatics and no longer represent an infectious challenge. Only when the capacity of the alveolar macrophages to ingest or kill the microorganisms is exceeded does clinical pneumonia become manifest. In that situation, the alveolar macrophages initiate the inflammatory response to bolster lower respiratory tract defenses. The host inflammatory response, rather than proliferation of microorganisms, triggers the clinical syndrome of pneumonia. The release of inflammatory mediators, such as interleukin 1 and tumor necrosis factor, results in fever. Chemokines, such as interleukin 8 and granulocyte colony-stimulating factor, stimulate the release of neutrophils and their attraction to the lung, producing both peripheral leukocytosis and increased purulent secretions. Inflammatory mediators released by macrophages and the newly recruited neutrophils create an alveolar capillary leak equivalent to that seen in the acute respiratory distress syndrome, although in pneumonia this leak is localized (at least initially). Even erythrocytes can cross the alveolar-capillary membrane, with consequent hemoptysis. The capillary leak results in a radiographic infiltrate and rales detectable on auscultation, and hypoxemia results from alveolar filling. Moreover, some bacterial pathogens appear to interfere with the hypoxemic vasoconstriction that would normally occur with fluid-filled alveoli, and this interference can result in severe hypoxemia. Increased respiratory drive in the systemic inflammatory response syndrome (Chap. 325) leads to respiratory alkalosis. Decreased compliance due to capillary leak, hypoxemia, increased respiratory drive, increased secretions, and occasionally infection-related bronchospasm all lead to dyspnea. If severe enough, the changes in lung mechanics secondary to reductions in lung volume and compliance and the intrapulmonary shunting of blood may cause respiratory failure and the patient’s death.
Classic pneumonia evolves through a series of pathologic changes. The initial phase is one of edema, with the presence of a proteinaceous exudate—and often of bacteria—in the alveoli. This phase is rarely evident in clinical or autopsy specimens because of the rapid transition to the red hepatization phase. The presence of erythrocytes in the cellular intraalveolar exudate gives this second stage its name, but neutrophil influx is more important with regard to host defense. Bacteria are occasionally seen in pathologic specimens collected during this phase. In the third phase, gray hepatization, no new erythrocytes are extravasating, and those already present have been lysed and degraded. The neutrophil is the predominant cell, fibrin deposition is abundant, and bacteria have disappeared. This phase corresponds with successful containment of the infection and improvement in gas exchange. In the final phase, resolution, the macrophage reappears as the dominant cell type in the alveolar space, and the debris of neutrophils, bacteria, and fibrin has been cleared, as has the inflammatory response.
This pattern has been described best for lobar pneumococcal pneumonia and may not apply to pneumonia of all etiologies, especially viral or Pneumocystis pneumonia. In VAP, respiratory bronchiolitis may precede the development of a radiologically apparent infiltrate. Because of the microaspiration mechanism, a bronchopneumonia pattern is most common in nosocomial pneumonias, whereas a lobar pattern is more common in bacterial CAP. Despite the radiographic appearance, viral and Pneumocystis pneumonias represent alveolar rather than interstitial processes.
The extensive list of potential etiologic agents in CAP includes bacteria, fungi, viruses, and protozoa. Newly identified pathogens include metapneumoviruses, the coronaviruses responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, and community-acquired strains of methicillin-resistant Staphylococcus aureus (MRSA). Most cases of CAP, however, are caused by relatively few pathogens (Table 153-2). Although Streptococcus pneumoniae is most common, other organisms also must be considered in light of the patient’s risk factors and severity of illness. Separation of potential agents into either “typical” bacterial pathogens or “atypical” organisms may be helpful. The former category includes S. pneumoniae, Haemophilus influenzae, and (in selected patients) S. aureus and gram-negative bacilli such as Klebsiella pneumoniae and Pseudomonas aeruginosa. The “atypical” organisms include Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species (in inpatients) as well as respiratory viruses such as influenza viruses, adenoviruses, human metapneumovirus, and respiratory syncytial viruses. Viruses may be responsible for a large proportion of CAP cases that require hospital admission, even in adults. Atypical organisms cannot be cultured on standard media or seen on Gram’s stain. The frequency and importance of atypical pathogens have significant implications for therapy. These organisms are intrinsically resistant to all β-lactam agents and must be treated with a macrolide, a fluoroquinolone, or a tetracycline. In the ∼10–15% of CAP cases that are polymicrobial, the etiology usually includes a combination of typical and atypical pathogens.
TABLE 153-2Microbial Causes of Community-Acquired Pneumonia, by Site of Care ||Download (.pdf) TABLE 153-2Microbial Causes of Community-Acquired Pneumonia, by Site of Care
| ||Hospitalized Patients |
|Outpatients ||Non-ICU ||ICU |
|Streptococcus pneumoniae ||S. pneumoniae ||S. pneumoniae |
|Mycoplasma pneumoniae ||M. pneumoniae ||Staphylococcus aureus |
|Haemophilus influenzae ||Chlamydia pneumoniae ||Legionella spp. |
|C. pneumoniae ||H. influenzae ||Gram-negative bacilli |
|Respiratory virusesa ||Legionella spp. ||H. influenzae |
| ||Respiratory virusesa || |
Anaerobes play a significant role only when an episode of aspiration has occurred days to weeks before presentation of pneumonia. The combination of an unprotected airway (e.g., in patients with alcohol or drug overdose or a seizure disorder) and significant gingivitis constitutes the major risk factor. Anaerobic pneumonias are often complicated by abscess formation and by significant empyemas or parapneumonic effusions.
S. aureus pneumonia is well known to complicate influenza infection. However, MRSA has been reported as the primary etiologic agent of CAP. While this entity is still relatively uncommon, clinicians must be aware of its potentially serious consequences, such as necrotizing pneumonia. Two important developments have led to this problem: the spread of MRSA from the hospital setting to the community and the emergence of genetically distinct strains of MRSA in the community. The former circumstance is more likely to result in HCAP, whereas the novel community-acquired MRSA (CA-MRSA) strains may infect healthy individuals with no association with health care.
Unfortunately, despite a careful history and physical examination as well as routine radiographic studies, the causative pathogen in a case of CAP is difficult to predict with any degree of certainty; in more than one-half of cases, a specific etiology is never determined. Nevertheless, epidemiologic and risk factors may suggest the involvement of certain pathogens (Table 153-3).
TABLE 153-3Epidemiologic Factors Suggesting Possible Causes of Community-Acquired Pneumonia ||Download (.pdf) TABLE 153-3Epidemiologic Factors Suggesting Possible Causes of Community-Acquired Pneumonia
|Factor ||Possible Pathogen(s) |
|Alcoholism ||Streptococcus pneumoniae, oral anaerobes, Klebsiella pneumoniae, Acinetobacter spp., Mycobacterium tuberculosis |
|COPD and/or smoking ||Haemophilus influenzae, Pseudomonas aeruginosa, Legionella spp., S. pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae |
|Structural lung disease (e.g., bronchiectasis) ||P. aeruginosa, Burkholderia cepacia, Staphylococcus aureus |
|Dementia, stroke, decreased level of consciousness ||Oral anaerobes, gram-negative enteric bacteria |
|Lung abscess ||CA-MRSA, oral anaerobes, endemic fungi, M. tuberculosis, atypical mycobacteria |
|Travel to Ohio or St. Lawrence river valleys ||Histoplasma capsulatum |
|Travel to southwestern United States ||Hantavirus, Coccidioides spp. |
|Travel to Southeast Asia ||Burkholderia pseudomallei, avian influenza virus |
|Stay in hotel or on cruise ship in previous 2 weeks ||Legionella spp. |
|Local influenza activity ||Influenza virus, S. pneumoniae, S. aureus |
|Exposure to bats or birds ||H. capsulatum |
|Exposure to birds ||Chlamydia psittaci |
|Exposure to rabbits ||Francisella tularensis |
|Exposure to sheep, goats, parturient cats ||Coxiella burnetii |
More than 5 million CAP cases occur annually in the United States; usually, 80% of the affected patients are treated as outpatients and 20% as inpatients. The mortality rate among outpatients is usually ≤1%, whereas among hospitalized patients the rate can range from ∼12% to 40%, depending on whether treatment is provided in or outside of the intensive care unit (ICU). CAP results in more than 1.2 million hospitalizations and more than 55,000 deaths annually. The overall yearly cost associated with CAP is estimated at $12 billion. The incidence rates are highest at the extremes of age. The overall annual rate in the United States is 12 cases/1000 persons, but the figure increases to 12–18/1000 among children <4 years of age and to 20/1000 among persons >60 years of age.
The risk factors for CAP in general and for pneumococcal pneumonia in particular have implications for treatment regimens. Risk factors for CAP include alcoholism, asthma, immunosuppression, institutionalization, and an age of ≥70 years. In the elderly, factors such as decreased cough and gag reflexes as well as reduced antibody and Toll-like receptor responses increase the likelihood of pneumonia. Risk factors for pneumococcal pneumonia include dementia, seizure disorders, heart failure, cerebrovascular disease, alcoholism, tobacco smoking, chronic obstructive pulmonary disease, and HIV infection. CA-MRSA pneumonia is more likely in patients with skin colonization or infection with CA-MRSA. Enterobacteriaceae tend to infect patients who have recently been hospitalized and/or received antibiotic therapy or who have comorbidities such as alcoholism, heart failure, or renal failure. P. aeruginosa is a particular problem in patients with severe structural lung disease, such as bronchiectasis, cystic fibrosis, or severe chronic obstructive pulmonary disease. Risk factors for Legionella infection include diabetes, hematologic malignancy, cancer, severe renal disease, HIV infection, smoking, male gender, and a recent hotel stay or ship cruise. (Many of these risk factors would now reclassify as HCAP some cases that were previously designated CAP.)
CAP can vary from indolent to fulminant in presentation and from mild to fatal in severity. Manifestations of progression and severity include both constitutional findings and those limited to the lung and associated structures. In light of the pathobiology of the disease, many of the findings are to be expected.
The patient is frequently febrile with tachycardia or may have a history of chills and/or sweats. Cough may be either nonproductive or productive of mucoid, purulent, or blood-tinged sputum. Gross hemoptysis is suggestive of CA-MRSA pneumonia. Depending on severity, the patient may be able to speak in full sentences or may be very short of breath. If the pleura is involved, the patient may experience pleuritic chest pain. Up to 20% of patients may have gastrointestinal symptoms such as nausea, vomiting, and/or diarrhea. Other symptoms may include fatigue, headache, myalgias, and arthralgias.
Findings on physical examination vary with the degree of pulmonary consolidation and the presence or absence of a significant pleural effusion. An increased respiratory rate and use of accessory muscles of respiration are common. Palpation may reveal increased or decreased tactile fremitus, and the percussion note can vary from dull to flat, reflecting underlying consolidated lung and pleural fluid, respectively. Crackles, bronchial breath sounds, and possibly a pleural friction rub may be heard on auscultation. The clinical presentation may not be so obvious in the elderly, who may initially display new-onset or worsening confusion and few other manifestations. Severely ill patients may have septic shock and evidence of organ failure.
When confronted with possible CAP, the physician must ask two questions: Is this pneumonia, and, if so, what is the likely etiology? The former question is typically answered by clinical and radiographic methods, whereas the latter requires the aid of laboratory techniques.
The differential diagnosis includes both infectious and noninfectious entities such as acute bronchitis, acute exacerbations of chronic bronchitis, heart failure, pulmonary embolism, hypersensitivity pneumonitis, and radiation pneumonitis. The importance of a careful history cannot be overemphasized. For example, known cardiac disease may suggest worsening pulmonary edema, while underlying carcinoma may suggest lung injury secondary to irradiation.
Unfortunately, the sensitivity and specificity of the findings on physical examination are less than ideal, averaging 58% and 67%, respectively. Therefore, chest radiography is often necessary to differentiate CAP from other conditions. Radiographic findings may include risk factors for increased severity (e.g., cavitation or multilobar involvement). Occasionally, radiographic results suggest an etiologic diagnosis. For example, pneumatoceles suggest infection with S. aureus, and an upper-lobe cavitating lesion suggests tuberculosis. CT may be of value in a patient with suspected postobstructive pneumonia caused by a tumor or foreign body or suspected cavitary disease. For outpatients, the clinical and radiologic assessments are usually all that is done before treatment for CAP is started since most laboratory results are not available soon enough to influence initial management significantly. In certain cases, the availability of rapid point-of-care outpatient diagnostic tests can be very important; for example, rapid diagnosis of influenza virus infection can prompt specific anti-influenza drug treatment and secondary prevention.
The etiology of pneumonia usually cannot be determined solely on the basis of clinical presentation. Except for CAP patients admitted to the ICU, no data exist to show that treatment directed at a specific pathogen is statistically superior to empirical therapy. The benefit of establishing a microbial etiology can therefore be questioned, particularly in light of the cost of diagnostic testing. However, a number of reasons can be advanced for attempting an etiologic diagnosis. Identification of an unexpected pathogen allows narrowing of the initial empirical regimen, thereby decreasing antibiotic selection pressure and lessening the risk of resistance. Pathogens with important public safety implications, such as Mycobacterium tuberculosis and influenza virus, may be found in some cases. Finally, without culture and susceptibility data, trends in resistance cannot be followed accurately, and appropriate empirical therapeutic regimens are harder to devise.
GRAM’S STAIN AND CULTURE OF SPUTUM
The main purpose of the sputum Gram’s stain is to ensure that a sample is suitable for culture. However, Gram’s staining may also identify certain pathogens (e.g., S. pneumoniae, S. aureus, and gram-negative bacteria) by their characteristic appearance. To be adequate for culture, a sputum sample must have >25 neutrophils and <10 squamous epithelial cells per low-power field. The sensitivity and specificity of the sputum Gram’s stain and culture are highly variable. Even in cases of proven bacteremic pneumococcal pneumonia, the yield of positive cultures from sputum samples is ≤50%.
Some patients, particularly elderly individuals, may not be able to produce an appropriate expectorated sputum sample. Others may already have started a course of antibiotics that can interfere with culture results at the time a sample is obtained. Inability to produce sputum can be a consequence of dehydration, and the correction of this condition may result in increased sputum production and a more obvious infiltrate on chest radiography. For patients admitted to the ICU and intubated, a deep-suction aspirate or bronchoalveolar lavage sample (obtained either via bronchoscopy or non-bronchoscopically) has a high yield on culture when sent to the microbiology laboratory as soon as possible. Since the etiologies in severe CAP are somewhat different from those in milder disease (Table 153-2), the greatest benefit of staining and culturing respiratory secretions is to alert the physician of unsuspected and/or resistant pathogens and to permit appropriate modification of therapy. Other stains and cultures (e.g., specific stains for M. tuberculosis or fungi) may be useful as well.
The yield from blood cultures, even when samples are collected before antibiotic therapy, is disappointingly low. Only 5–14% of cultures of blood from patients hospitalized with CAP are positive, and the most frequently isolated pathogen is S. pneumoniae. Since recommended empirical regimens all provide pneumococcal coverage, a blood culture positive for this pathogen has little, if any, effect on clinical outcome. However, susceptibility data may allow narrowing of antibiotic therapy in appropriate cases. Because of the low yield and the lack of significant impact on outcome, blood cultures are no longer considered de rigueur for all hospitalized CAP patients. Certain high-risk patients—including those with neutropenia secondary to pneumonia, asplenia, complement deficiencies, chronic liver disease, or severe CAP—should have blood cultured.
Two commercially available tests detect pneumococcal and Legionella antigen in urine. The test for Legionella pneumophila detects only serogroup 1, but this serogroup accounts for most community-acquired cases of Legionnaires’ disease in the United States. The sensitivity and specificity of the Legionella urine antigen test are as high as 90% and 99%, respectively. The pneumococcal urine antigen test also is quite sensitive and specific (80% and >90%, respectively). Although false-positive results can be obtained with samples from pneumococcus-colonized children, the test is generally reliable. Both tests can detect antigen even after the initiation of appropriate antibiotic therapy.
POLYMERASE CHAIN REACTION
Polymerase chain reaction (PCR) tests, which amplify a microorganism’s DNA or RNA, are available for a number of pathogens. PCR of nasopharyngeal swabs has become the standard for diagnosis of respiratory viral infection. In addition, PCR can detect the nucleic acid of Legionella species, M. pneumoniae, C. pneumoniae, and mycobacteria. In patients with pneumococcal pneumonia, an increased bacterial load in whole blood documented by PCR is associated with an increased risk of septic shock, the need for mechanical ventilation, and death. Clinical availability of such a test could conceivably help identify patients suitable for ICU admission.
A fourfold rise in specific IgM antibody titer between acute- and convalescent-phase serum samples is generally considered diagnostic of infection with the pathogen in question. In the past, serologic tests were used to help identify atypical pathogens as well as selected unusual organisms such as Coxiella burnetii. Recently, however, they have fallen out of favor because of the time required to obtain a final result for the convalescent-phase sample.
A number of substances can serve as markers of severe inflammation. The two currently in use are C-reactive protein (CRP) and procalcitonin (PCT). Levels of these acute-phase reactants increase in the presence of an inflammatory response, particularly to bacterial pathogens. CRP may be of use in the identification of worsening disease or treatment failure, and PCT may play a role in determining the need for antibacterial therapy. These tests should not be used on their own but, when interpreted in conjunction with other findings from the history, physical examination, radiology, and laboratory tests, may help with antibiotic stewardship and appropriate management of seriously ill patients with CAP.
TREATMENT Community-Acquired Pneumonia SITE OF CARE
The cost of inpatient management exceeds that of outpatient treatment by a factor of 20, and hospitalization accounts for most CAP-related expenditures. Thus the decision to admit a patient with CAP to the hospital has considerable implications. Certain patients clearly can be managed at home, and others clearly require treatment in the hospital, but the choice is sometimes difficult. Tools that objectively assess the risk of adverse outcomes, including severe illness and death, can minimize unnecessary hospital admissions. There are currently two sets of criteria: the Pneumonia Severity Index (PSI), a prognostic model used to identify patients at low risk of dying; and the CURB-65 criteria, a severity-of-illness score.
To determine the PSI, points are given for 20 variables, including age, coexisting illness, and abnormal physical and laboratory findings. On the basis of the resulting score, patients are assigned to one of five classes with the following mortality rates: class 1, 0.1%; class 2, 0.6%; class 3, 2.8%; class 4, 8.2%; and class 5, 29.2%. Determination of the PSI is often impractical in a busy emergency-department setting because of the number of variables that must be assessed. However, clinical trials demonstrate that routine use of the PSI results in lower admission rates for class 1 and class 2 patients. Patients in class 3 could ideally be admitted to an observation unit until a further decision can be made.
The CURB-65 criteria include five variables: confusion (C); urea >7 mmol/L (U); respiratory rate ≥30/min (R); blood pressure, systolic ≤90 mmHg or diastolic ≤60 mmHg (B); and age ≥65 years. Patients with a score of 0, among whom the 30-day mortality rate is 1.5%, can be treated outside the hospital. With a score of 2, the 30-day mortality rate is 9.2%, and patients should be admitted to the hospital. Among patients with scores of ≥3, mortality rates are 22% overall; these patients may require ICU admission.
It is not clear which assessment tool is superior. Whichever system is used, these objective criteria must always be tempered by careful consideration of factors relevant to individual patients, including the ability to comply reliably with an oral antibiotic regimen and the resources available to the patient outside the hospital.
Neither PSI nor CURB-65 is accurate in determining the need for ICU admission. Septic shock or respiratory failure in the emergency department is an obvious indication for ICU care. However, mortality rates are higher among less ill patients who are admitted to the floor and then deteriorate than among equally ill patients monitored in the ICU. A variety of scores have been proposed to identify patients most likely to have early deterioration (Table 153-4). Most factors in these scores are similar to the minor severity criteria proposed by the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) in their guidelines for the management of CAP. ANTIBIOTIC RESISTANCE
Antimicrobial resistance is a significant problem that threatens to diminish our therapeutic armamentarium. Misuse of antibiotics results in increased antibiotic selection pressure that can affect resistance locally or even globally by clonal dissemination. For CAP, the main resistance issues currently involve S. pneumoniae and CA-MRSA. S. pneumoniae
In general, pneumococcal resistance is acquired (1) by direct DNA incorporation and remodeling resulting from contact with closely related oral commensal bacteria, (2) by the process of natural transformation, or (3) by mutation of certain genes.
The minimal inhibitory concentration (MIC) cutoffs for penicillin in pneumonia are ≤2 μg/mL for susceptibility, >2–4 μg/mL for intermediate, and ≥8 μg/mL for resistant. A change in susceptibility thresholds resulted in a dramatic decrease in the proportion of pneumococcal isolates considered nonsusceptible. For meningitis, MIC thresholds remain at the former higher levels. Fortunately, resistance to penicillin appeared to plateau even before the change in MIC thresholds. Pneumococcal resistance to β-lactam drugs is due solely to low-affinity penicillin-binding proteins. Risk factors for penicillin-resistant pneumococcal infection include recent antimicrobial therapy, an age of <2 years or >65 years, attendance at day-care centers, recent hospitalization, and HIV infection.
In contrast to penicillin resistance, resistance to macrolides is increasing through several mechanisms. Target-site modification caused by ribosomal methylation in 23S rRNA encoded by the ermB gene results in high-level resistance (MICs, ≥64 μg/mL) to macrolides, lincosamides, and streptogramin B–type antibiotics. The efflux mechanism encoded by the mef gene (M phenotype) is usually associated with low-level resistance (MICs, 1–32 μg/mL). These two mechanisms account for ∼45% and ∼65%, respectively, of resistant pneumococcal isolates in the United States. High-level resistance to macrolides is more common in Europe, whereas lower-level resistance predominates in North America.
Pneumococcal resistance to fluoroquinolones (e.g., ciprofloxacin and levofloxacin) has been reported. Changes can occur in one or both target sites (topoisomerases II and IV) from mutations in the gyrA and parC genes, respectively. In addition, an efflux pump may play a role in pneumococcal resistance to fluoroquinolones.
Isolates resistant to drugs from three or more antimicrobial classes with different mechanisms of action are considered MDR strains. The propensity for an association of pneumococcal resistance to penicillin with reduced susceptibility to other drugs, such as macrolides, tetracyclines, and trimethoprim-sulfamethoxazole, also is of concern. In the United States, 58.9% of penicillin-resistant pneumococcal isolates from blood are also resistant to macrolides.
The most important risk factor for antibiotic-resistant pneumococcal infection is use of a specific antibiotic within the previous 3 months. Therefore, a patient’s history of prior antibiotic treatment is a critical factor in avoiding the use of an inappropriate antibiotic. CA-MRSA
CAP due to MRSA may be caused by the classic hospital-acquired strains or by the more recently identified, genotypically and phenotypically distinct community-acquired strains. Most infections with the former strains have been acquired either directly or indirectly by contact with the health care environment and would now be classified as HCAP. However, in some hospitals, the CA-MRSA strains are displacing the classic hospital-acquired strains—a trend suggesting that the newer strains may be more robust and blurring this distinction.
Methicillin resistance in S. aureus is determined by the mecA gene, which encodes for resistance to all β-lactam drugs. At least five staphylococcal chromosomal cassette mec (SCCmec) types have been described. The typical hospital-acquired strain usually has type II or III, whereas CA-MRSA has a type IV SCCmec element. CA-MRSA isolates tend to be less resistant than the older hospital-acquired strains and are often susceptible to trimethoprim-sulfamethoxazole, clindamycin, and tetracycline in addition to vancomycin and linezolid. However, the most important distinction is that CA-MRSA strains also carry genes for superantigens, such as enterotoxins B and C and Panton-Valentine leukocidin, a membrane-tropic toxin that can create cytolytic pores in polymorphonuclear neutrophils, monocytes, and macrophages. Gram-Negative Bacilli
A detailed discussion of resistance among gram-negative bacilli is beyond the scope of this chapter (Chap. 186). Fluoroquinolone resistance among isolates of Escherichia coli from the community appears to be increasing. Enterobacter species are typically resistant to cephalosporins; the drugs of choice for use against these bacteria are usually fluoroquinolones or carbapenems. Similarly, when infections due to bacteria producing extended-spectrum β-lactamases are documented or suspected, a fluoroquinolone or a carbapenem should be used; these MDR strains are more likely to be involved in HCAP. INITIAL ANTIBIOTIC MANAGEMENT
Since the etiology of CAP is rarely known at the outset of treatment, initial therapy is usually empirical, designed to cover the most likely pathogens (Table 153-5). In all cases, antibiotic treatment should be initiated as expeditiously as possible. The CAP treatment guidelines in the United States (summarized in Table 153-5) represent joint statements from the IDSA and the ATS; the Canadian guidelines come from the Canadian Infectious Disease Society and the Canadian Thoracic Society. In all these guidelines, coverage is always provided for the pneumococcus and the atypical pathogens. In contrast, guidelines from some European countries do not always include atypical coverage based on local epidemiologic data. The U.S./Canadian approach is supported by retrospective data derived from administrative databases including thousands of patients. Atypical pathogen coverage provided by the addition of a macrolide to a cephalosporin or by the use of a fluoroquinolone alone has been consistently associated with a significant reduction in mortality rates compared with those for β-lactam coverage alone.
Therapy with a macrolide or a fluoroquinolone within the previous 3 months is associated with an increased likelihood of infection with a resistant strain of S. pneumoniae. For this reason, a fluoroquinolone-based regimen should be used for patients recently given a macrolide, and vice versa (Table 153-5).
Once the etiologic agent(s) and susceptibilities are known, therapy may be altered to target the specific pathogen(s). However, this decision is not always straightforward. If blood cultures yield S. pneumoniae sensitive to penicillin after 2 days of treatment with a macrolide plus a β-lactam or with a fluoroquinolone alone, should therapy be switched to penicillin alone? The concern here is that a β-lactam alone would not be effective in the potential 15% of cases with atypical co-infection. No standard approach exists. In all cases, the individual patient and the various risk factors must be considered.
Management of bacteremic pneumococcal pneumonia also is controversial. Data from nonrandomized studies suggest that combination therapy (especially macrolide/β-lactam) is associated with a lower mortality rate than monotherapy, particularly in severely ill patients. The exact reason is unknown, but possible explanations include an additive or synergistic antibacterial effect, antimicrobial tolerance, atypical co-infection, or the immunomodulatory effects of the macrolides.
For CAP patients admitted to the ICU, the risk of infection with P. aeruginosa or CA-MRSA is increased. Empirical coverage should be considered when a patient has risk factors or a Gram’s stain suggestive of these pathogens (Table 153–5). If CA-MRSA is suspected, either linezolid or vancomycin can be added to the initial empirical regimen; however, there is increasing concern about vancomycin’s loss of potency against MRSA, poor penetration into epithelial lining fluid, and lack of effect on toxin production relative to linezolid.
Although hospitalized patients have traditionally received initial therapy by the IV route, some drugs—particularly the fluoroquinolones—are very well absorbed and can be given orally from the outset to select patients. For patients initially treated IV, a switch to oral treatment is appropriate as long as the patient can ingest and absorb the drugs, is hemodynamically stable, and is showing clinical improvement.
The duration of treatment for CAP has generated considerable interest. Patients were previously treated for 10–14 days, but studies with fluoroquinolones and telithromycin suggest that a 5-day course is sufficient for otherwise uncomplicated CAP. Even a single dose of ceftriaxone has been associated with a significant cure rate. A longer course may be required for patients with bacteremia, metastatic infection, or infection with a virulent pathogen such as P. aeruginosa or CA-MRSA. GENERAL CONSIDERATIONS
In addition to appropriate antimicrobial therapy, certain general considerations apply in dealing with CAP, HCAP, or HAP/VAP. Adequate hydration, oxygen therapy for hypoxemia, and assisted ventilation when necessary are critical to successful treatment. Patients with severe CAP who remain hypotensive despite fluid resuscitation may have adrenal insufficiency and may respond to glucocorticoid treatment. The value of adjunctive therapy, such as glucocorticoids, statins, and angiotensin-converting enzyme inhibitors, remains unproven in the management of CAP. Failure to Improve
Patients slow to respond to therapy should be reevaluated at about day 3 (sooner if their condition is worsening rather than simply not improving), and several possible scenarios should be considered. A number of noninfectious conditions mimic pneumonia, including pulmonary edema, pulmonary embolism, lung carcinoma, radiation and hypersensitivity pneumonitis, and connective tissue disease involving the lungs. If the patient truly has CAP and empirical treatment is aimed at the correct pathogen, lack of response may be explained in a number of ways. The pathogen may be resistant to the drug selected, or a sequestered focus (e.g., lung abscess or empyema) may be blocking access of the antibiotic(s) to the pathogen. The patient may be getting either the wrong drug or the correct drug at the wrong dose or frequency of administration. Another possibility is that CAP is the correct diagnosis but an unsuspected pathogen (e.g., CA-MRSA, M. tuberculosis, or a fungus) is the cause. Nosocomial superinfections—both pulmonary and extrapulmonary—are other possible explanations for a patient’s failure to improve or deterioration. In all cases of delayed response or deteriorating condition, the patient must be carefully reassessed and appropriate studies initiated, possibly including such diverse procedures as CT or bronchoscopy. Complications
As in other severe infections, common complications of severe CAP include respiratory failure, shock and multiorgan failure, coagulopathy, and exacerbation of comorbid illnesses. Three particularly noteworthy conditions are metastatic infection, lung abscess, and complicated pleural effusion. Metastatic infection (e.g., brain abscess or endocarditis) is very unusual and will require a high degree of suspicion and a detailed workup for proper treatment. Lung abscess may occur in association with aspiration or with infection caused by a single CAP pathogen, such as CA-MRSA, P. aeruginosa, or (rarely) S. pneumoniae. Aspiration pneumonia is typically a polymicrobial infection involving both aerobes and anaerobes. A significant pleural effusion should be tapped for both diagnostic and therapeutic purposes. If the fluid has a pH of <7, a glucose level of <2. 2 mmol/L, and a lactate dehydrogenase concentration of >1000 U/L or if bacteria are seen or cultured, then it should be completely drained; a chest tube is often required and video-assisted thoracoscopy may be needed for late treatment or difficult cases. Follow-Up
Fever and leukocytosis usually resolve within 2–4 days in otherwise healthy patients with CAP, but physical findings may persist longer. Chest radiographic abnormalities are slowest to resolve (4–12 weeks), with the speed of clearance depending on the patient’s age and underlying lung disease. Patients may be discharged from the hospital once their clinical conditions, including comorbidities, are stable. The site of residence after discharge (nursing home, home with family, home alone) is an important discharge timing consideration, particularly for elderly patients. For a hospitalized patient, a follow-up radiograph ∼4–6 weeks later is recommended. If relapse or recurrence is documented, particularly in the same lung segment, the possibility of an underlying neoplasm must be considered.
TABLE 153-4Risk Factors for Early Deterioration in CAP ||Download (.pdf) TABLE 153-4Risk Factors for Early Deterioration in CAP
Severe hypoxemia (arterial saturation <90%)
Severe acidosis (pH <7.30)
Severe tachypnea (>30 breaths/min)
TABLE 153-5Empirical Antibiotic Treatment of Community-Acquired Pneumonia ||Download (.pdf) TABLE 153-5Empirical Antibiotic Treatment of Community-Acquired Pneumonia
|1. Previously healthy and no antibiotics in past 3 months |
|• A macrolide (clarithromycin [500 mg PO bid] or azithromycin [500 mg PO once, then 250 mg qd]) or |
|• Doxycycline (100 mg PO bid) |
|2. Comorbidities or antibiotics in past 3 months: select an alternative from a different class |
|• A respiratory fluoroquinolone (moxifloxacin [400 mg PO qd], gemifloxacin [320 mg PO qd], levofloxacin [750 mg PO qd]) or |
|• A β-lactam (preferred: high-dose amoxicillin [1 g tid] or amoxicillin/clavulanate [2 g bid]; alternatives: ceftriaxone [1–2 g IV qd], cefpodoxime [200 mg PO bid], cefuroxime [500 mg PO bid]) plus a macrolidea |
|3. In regions with a high rate of “high-level” pneumococcal macrolide resistance,b consider alternatives listed above for patients with comorbidities. |
|Inpatients, Non-ICU |
|• A respiratory fluoroquinolone (e.g., moxifloxacin [400 mg PO or IV qd] or levofloxacin [750 mg PO or IV qd]) |
|• A β-lactamc (e.g., ceftriaxone [1–2 g IV qd], ampicillin [1–2 g IV q4–6h], cefotaxime [1–2 g IV q8h], ertapenem [1 g IV qd]) plus a macrolided (e.g., oral clarithromycin or azithromycin [as listed above] or IV azithromycin [1 g once, then 500 mg qd]) |
|Inpatients, ICU |
|• A β-lactame (e.g., ceftriaxone [2 g IV qd], ampicillin-sulbactam [2 g IV q8h], or cefotaxime [1–2 g IV q8h]) plus either azithromycin or a fluoroquinolone (as listed above for inpatients, non-ICU) |
|Special Concerns |
|If Pseudomonas is a consideration: |
|• An antipseudomonal β-lactam (e.g., piperacillin/tazobactam [4. 5 g IV q6h], cefepime [1–2 g IV q12h], imipenem [500 mg IV q6h], meropenem [1 g IV q8h]) plus either ciprofloxacin (400 mg IV q12h) or levofloxacin (750 mg IV qd) |
|• The above β-lactams plus an aminoglycoside (amikacin [15 mg/kg qd] or tobramycin [1. 7 mg/kg qd]) plus azithromycin |
|• The above β-lactamsf plus an aminoglycoside plus an antipneumococcal fluoroquinolone |
|If CA-MRSA is a consideration: |
|• Add linezolid (600 mg IV q12h) or vancomycin (15 mg/kg q12h initially, with adjusted doses) |
The prognosis of CAP depends on the patient’s age, comorbidities, and site of treatment (inpatient or outpatient). Young patients without comorbidity do well and usually recover fully after ~2 weeks. Older patients and those with comorbid conditions can take several weeks longer to recover fully. The overall mortality rate for the outpatient group is <1%. For patients requiring hospitalization, the overall mortality rate is estimated at 10%, with ~50% of deaths directly attributable to pneumonia.
The main preventive measure is vaccination (Chap. 148). Recommendations of the Advisory Committee on Immunization Practices should be followed for influenza and pneumococcal vaccines.
A pneumococcal polysaccharide vaccine (PPV23) and a protein conjugate pneumococcal vaccine (PCV13) are available in the United States. The former product contains capsular material from 23 pneumococcal serotypes; in the latter, capsular polysaccharide from 13 of the most frequent pneumococcal pathogens affecting children is linked to an immunogenic protein. PCV13 produces T cell–dependent antigens that result in long-term immunologic memory. Administration of this vaccine to children has led to an overall decrease in the prevalence of antimicrobial-resistant pneumococci and in the incidence of invasive pneumococcal disease among both children and adults. However, vaccination can be followed by the replacement of vaccine serotypes with nonvaccine serotypes, as was seen with serotypes 19A and 35B after introduction of the original 7-valent conjugate vaccine. PCV13 now is also recommended for the elderly and for younger immunocompromised patients. Because of an increased risk of pneumococcal infection, even among patients without obstructive lung disease, smokers should be strongly encouraged to stop smoking.
Two forms of influenza vaccine are available: intramuscular inactivated vaccine and intranasal live-attenuated cold-adapted vaccine. The latter is contraindicated in immunocompromised patients. In the event of an influenza outbreak, unprotected patients at risk from complications should be vaccinated immediately and given chemoprophylaxis with either oseltamivir or zanamivir for 2 weeks—i.e., until vaccine-induced antibody levels are sufficiently high.
HEALTH CARE–ASSOCIATED PNEUMONIA
HCAP represents a transition between classic CAP and typical HAP. The definition of HCAP is still in some flux because of a lack of consistent large-scale studies. Several early studies were limited to patients with culture-positive pneumonia. In these studies, the incidence of MDR pathogens in HCAP was as high as or higher than in HAP/VAP. MRSA in particular was more common in HCAP than in traditional HAP/VAP. Conversely, prospective studies in nontertiary-care centers have found a low incidence of MDR pathogens in HCAP.
The patients at greatest risk for HCAP are not well defined. Patients from nursing homes are not always at elevated risk for infection with MDR pathogens. Careful evaluation of nursing home residents with pneumonia suggests that their risk of MDR infection is low if they have not recently received antibiotics and are independent in most activities of daily living. Recent hospitalization (i.e., in the preceding 90 days) is also a major risk factor for infection with MDR pathogens. Conversely, nursing home patients are at increased risk of infection with influenza virus and other atypical pneumonia pathogens. Undue concern about MDR pathogens occasionally results in failure to cover atypical pathogens when treating nursing home patients. In addition, patients receiving home infusion therapy or undergoing chronic dialysis are probably at particular risk for MRSA pneumonia but may not be at greater risk for infection with Pseudomonas or Acinetobacter than are other patients who develop CAP.
In general, the management of HCAP due to MDR pathogens is similar to that of MDR HAP/VAP. This topic will therefore be covered in subsequent sections on HAP and VAP. The prognosis of HCAP is intermediate between that of CAP and VAP and is closer to that of HAP.
Most hospital-acquired pneumonia research has focused on VAP. However, the information and principles based on this research can be applied to non-ICU HAP and HCAP as well. The greatest difference between VAP and HCAP/HAP studies is the dependence on expectorated sputum for a microbiologic diagnosis of VAP (as for that of CAP), which is further complicated by frequent colonization by pathogens in patients with HAP or HCAP. Therefore, most of the literature has focused on HCAP or HAP resulting in intubation, where, once again, access to the lower respiratory tract facilitates an etiologic diagnosis.
Potential etiologic agents of VAP include both MDR and non-MDR bacterial pathogens (Table 153-6). The non-MDR group is nearly identical to the pathogens found in severe CAP (Table 153-2); it is not surprising that such pathogens predominate if VAP develops in the first 5–7 days of the hospital stay. However, if patients have other risk factors for HCAP, MDR pathogens are a consideration, even early in the hospital course. The relative frequency of individual MDR pathogens can vary significantly from hospital to hospital and even between different critical care units within the same institution. Most hospitals have problems with P. aeruginosa and MRSA, but other MDR pathogens are often institution-specific. Less commonly, fungal and viral pathogens cause VAP, usually affecting severely immunocompromised patients. Rarely, community-associated viruses cause mini-epidemics, usually when introduced by ill health care workers.
Pneumonia is a common complication among patients requiring mechanical ventilation. Prevalence estimates vary between 6 and 52 cases per 100 patients, depending on the population studied. On any given day in the ICU, an average of 10% of patients will have pneumonia—VAP in the overwhelming majority of cases. The frequency of diagnosis is not static but changes with the duration of mechanical ventilation, with the highest hazard ratio in the first 5 days and a plateau in additional cases (1% per day) after ~2 weeks. However, the cumulative rate among patients who remain ventilated for as long as 30 days is as high as 70%. These rates often do not reflect the recurrence of VAP in the same patient. Once a ventilated patient is transferred to a chronic-care facility or to home, the incidence of pneumonia drops significantly, especially in the absence of other risk factors for pneumonia. However, in chronic ventilator units, purulent tracheobronchitis becomes a significant issue, often interfering with efforts to wean patients off mechanical ventilation (Chap. 323).
TABLE 153-6Microbiologic Causes of Ventilator-Associated Pneumonia ||Download (.pdf) TABLE 153-6Microbiologic Causes of Ventilator-Associated Pneumonia
|Non-MDR Pathogens ||MDR Pathogens |
Other Streptococcus spp.
Three factors are critical in the pathogenesis of VAP: colonization of the oropharynx with pathogenic microorganisms, aspiration of these organisms from the oropharynx into the lower respiratory tract, and compromise of the normal host defense mechanisms. Most risk factors and their corresponding prevention strategies pertain to one of these three factors (Table 153-7).
TABLE 153-7Pathogenic Mechanisms and Corresponding Prevention Strategies for Ventilator-Associated Pneumonia ||Download (.pdf) TABLE 153-7Pathogenic Mechanisms and Corresponding Prevention Strategies for Ventilator-Associated Pneumonia
|Pathogenic Mechanism ||Prevention Strategy |
|Oropharyngeal colonization with pathogenic bacteria || |
| Elimination of normal flora ||Avoidance of prolonged antibiotic courses |
| Large-volume oropharyngeal aspiration around time of intubation ||Short course of prophylactic antibiotics for comatose patientsa |
| Gastroesophageal reflux ||Postpyloric enteral feedingb; avoidance of high gastric residuals, prokinetic agents |
| Bacterial overgrowth of stomach ||Avoidance of prophylactic agents that raise gastric pHb; selective decontamination of digestive tract with nonabsorbable antibioticsb |
|Cross-infection from other colonized patients ||Hand washing, especially with alcohol-based hand rub; intensive infection control educationa; isolation; proper cleaning of reusable equipment |
|Large-volume aspiration ||Endotracheal intubation; rapid-sequence intubation technique; avoidance of sedation; decompression of small-bowel obstruction |
|Microaspiration around endotracheal tube || |
| Endotracheal intubation ||Noninvasive ventilationa |
| Prolonged duration of ventilation ||Daily awakening from sedation,a weaning protocolsa |
| Abnormal swallowing function ||Early percutaneous tracheostomya |
| Secretions pooled above endotracheal tube ||Head of bed elevateda; continuous aspiration of subglottic secretions with specialized endotracheal tubea; avoidance of reintubation; minimization of sedation and patient transport |
|Altered lower respiratory host defenses ||Tight glycemic controlb; lowering of hemoglobin transfusion threshold |
The most obvious risk factor is the endotracheal tube, which bypasses the normal mechanical factors preventing aspiration. While the presence of an endotracheal tube may prevent large-volume aspiration, microaspiration is actually exacerbated by secretions pooling above the cuff. The endotracheal tube and the concomitant need for suctioning can damage the tracheal mucosa, thereby facilitating tracheal colonization. In addition, pathogenic bacteria can form a glycocalyx biofilm on the tube’s surface that protects them from both antibiotics and host defenses. The bacteria can also be dislodged during suctioning and can reinoculate the trachea, or tiny fragments of glycocalyx can embolize to distal airways, carrying bacteria with them.
In a high percentage of critically ill patients, the normal oropharyngeal flora is replaced by pathogenic microorganisms. The most important risk factors are antibiotic selection pressure, cross-infection from other infected/colonized patients or contaminated equipment, and malnutrition. Of these factors, antibiotic exposure poses the greatest risk by far. Pathogens such as P. aeruginosa almost never cause infection in patients without prior exposure to antibiotics. The recent emphasis on hand hygiene has lowered the cross-infection rate.
How the lower respiratory tract defenses become overwhelmed remains poorly understood. Almost all intubated patients experience microaspiration and are at least transiently colonized with pathogenic bacteria. However, only around one-third of colonized patients develop VAP. Colony counts increase to high levels, sometimes days before the development of clinical pneumonia; these increases suggest that the final step in VAP development, independent of aspiration and oropharyngeal colonization, is the overwhelming of host defenses. Severely ill patients with sepsis and trauma appear to enter a state of immunoparalysis several days after admission to the ICU—a time that corresponds to the greatest risk of developing VAP. The mechanism of this immunosuppression is not clear, although several factors have been suggested. Hyperglycemia affects neutrophil function, and trials suggest that keeping the blood sugar level close to normal with exogenous insulin may have beneficial effects, including a decreased risk of infection. More frequent transfusions also adversely affect the immune response.
The clinical manifestations are generally the same in VAP as in all other forms of pneumonia: fever, leukocytosis, increase in respiratory secretions, and pulmonary consolidation on physical examination, along with a new or changing radiographic infiltrate. The frequency of abnormal chest radiographs before the onset of pneumonia in intubated patients and the limitations of portable radiographic technique make interpretation of radiographs more difficult than in patients who are not intubated. Other clinical features may include tachypnea, tachycardia, worsening oxygenation, and increased minute ventilation.
No single set of criteria is reliably diagnostic of pneumonia in a ventilated patient. The inability to identify such patients compromises efforts to prevent and treat VAP and even calls into question estimates of the impact of VAP on mortality rates.
Application of clinical criteria consistently results in overdiagnosis of VAP, largely because of three common findings in at-risk patients: (1) tracheal colonization with pathogenic bacteria in patients with endotracheal tubes, (2) multiple alternative causes of radiographic infiltrates in mechanically ventilated patients, and (3) the high frequency of other sources of fever in critically ill patients. The differential diagnosis of VAP includes a number of entities such as atypical pulmonary edema, pulmonary contusion, alveolar hemorrhage, hypersensitivity pneumonitis, acute respiratory distress syndrome, and pulmonary embolism. Clinical findings in ventilated patients with fever and/or leukocytosis may have alternative causes, including antibiotic-associated diarrhea, sinusitis, urinary tract infection, pancreatitis, and drug fever. Conditions mimicking pneumonia are often documented in patients in whom VAP has been ruled out by accurate diagnostic techniques. Most of these alternative diagnoses do not require antibiotic treatment; require antibiotics different from those used to treat VAP; or require some additional intervention, such as surgical drainage or catheter removal, for optimal management.
This diagnostic dilemma has led to debate and controversy. The major question is whether a quantitative-culture approach as a means of eliminating false-positive clinical diagnoses is superior to the clinical approach enhanced by principles learned from quantitative-culture studies. The most recent IDSA/ATS guidelines for HAP/VAP suggest that either approach is clinically valid.
The essence of the quantitative-culture approach is to discriminate between colonization and true infection by determining the bacterial burden. The more distal in the respiratory tree the diagnostic sampling, the more specific the results and therefore the lower the threshold of growth necessary to diagnose pneumonia and exclude colonization. For example, a quantitative endotracheal aspirate yields proximate samples, and the diagnostic threshold is 106 cfu/mL. The protected specimen brush method, in contrast, obtains distal samples and has a threshold of 103 cfu/mL. Conversely, sensitivity declines as more distal secretions are obtained, especially when they are collected blindly (i.e., by a technique other than bronchoscopy). Additional tests that may increase the diagnostic yield include Gram’s staining, differential cell counts, staining for intracellular organisms, and detection of local protein levels elevated in response to infection.
The Achilles heel of the quantitative approach is the effect of antibiotic therapy. With sensitive microorganisms, a single antibiotic dose can reduce colony counts below the diagnostic threshold. Recent changes in antibiotic therapy are the most significant. After 3 days, the operating characteristics of the tests are almost the same as if no antibiotic therapy has been given. Conversely, colony counts above the diagnostic threshold during antibiotic therapy suggest that the current antibiotics are ineffective. Even the normal host response may be sufficient to reduce quantitative-culture counts below the diagnostic threshold if sampling is delayed. In short, expertise in quantitative-culture techniques is critical, with a specimen obtained as soon as pneumonia is suspected and before antibiotic therapy is initiated or changed.
In a study comparing the quantitative with the clinical approach, use of bronchoscopic quantitative cultures resulted in significantly less antibiotic use at 14 days after study entry and in lower rates of mortality and severity-adjusted mortality at 28 days. In addition, more alternative sites of infection were found in patients randomized to the quantitative-culture strategy. A critical aspect of this study was that antibiotic treatment was initiated only in patients whose gram-stained respiratory sample was positive or who displayed signs of hemodynamic instability. Fewer than one-half as many patients were treated for pneumonia in the bronchoscopy group, and only one-third as many microorganisms were cultured.
TABLE 153-8Clinical Pulmonary Infection Score (CPIS) ||Download (.pdf) TABLE 153-8Clinical Pulmonary Infection Score (CPIS)
|Criterion ||Score |
|Fever (°C) || |
| ≥38.5 but ≤38.9 ||1 |
| >39 or <36 ||2 |
|Leukocytosis || |
| <4000 or >11,000/μL ||1 |
| Bands >50% ||1 (additional) |
|Oxygenation (mmHg) || |
| PaO2/FIO2<250 and no ARDS ||2 |
|Chest radiograph || |
| Localized infiltrate ||2 |
| Patchy or diffuse infiltrate ||1 |
| Progression of infiltrate (no ARDS or CHF) ||2 |
|Tracheal aspirate || |
| Moderate or heavy growth ||1 |
| Same morphology on Gram’s stain ||1 (additional) |
|Maximal scorea ||12 |
The lack of specificity of a clinical diagnosis of VAP has led to efforts to improve the diagnostic criteria. The Clinical Pulmonary Infection Score (CPIS) was developed by weighting of the various clinical criteria usually used for the diagnosis of VAP (Table 153-8). Use of the CPIS allows the selection of low-risk patients who may need only short-course antibiotic therapy or no treatment at all. Moreover, studies have demonstrated that the absence of bacteria in gram-stained endotracheal aspirates makes pneumonia an unlikely cause of fever or pulmonary infiltrates. These findings, coupled with a heightened awareness of the alternative diagnoses possible in patients with suspected VAP, can prevent inappropriate overtreatment for pneumonia. Furthermore, data show that the absence of an MDR pathogen in tracheal aspirate cultures eliminates the need for MDR coverage when empirical antibiotic therapy is narrowed. Since the most likely explanations for the mortality benefit of bronchoscopic quantitative cultures are decreased antibiotic selection pressure (which reduces the risk of subsequent infection with MDR pathogens) and identification of alternative sources of infection, a clinical diagnostic approach that incorporates such principles may result in similar outcomes.
Other large randomized studies that did not demonstrate a similar beneficial impact of quantitative culture on outcomes did not tightly link antibiotic treatment to the results of quantitative culture and other tests. Given the conflicting results only partially explained by methodologic issues, the IDSA/ATS guidelines therefore suggest that the choice depends on availability and local expertise.
TREATMENT Ventilator-Associated Pneumonia
Many studies have demonstrated higher mortality rates with initially inappropriate empirical antibiotic therapy. The key to appropriate antibiotic management of VAP is an appreciation of the resistance patterns of the most likely pathogens in a given patient. ANTIBIOTIC RESISTANCE
If not for the higher risk of infection with MDR pathogens (Table 153-1), VAP could be treated with the same antibiotics used for severe CAP. However, antibiotic selection pressure leads to the frequent involvement of MDR pathogens by selecting either for drug-resistant isolates of common pathogens (MRSA and Enterobacteriaceae producing extended-spectrum β-lactamases or carbapenemases) or for intrinsically resistant pathogens (P. aeruginosa and Acinetobacter species). Frequent use of β-lactam drugs, especially cephalosporins, appears to be the major risk factor for infection with MRSA and extended-spectrum β-lactamase–positive strains.
P. aeruginosa has demonstrated the ability to develop resistance to all routinely used antibiotics. Unfortunately, even if initially sensitive, P. aeruginosa isolates also have a propensity to develop resistance during treatment. Either de-repression of resistance genes or selection of resistant clones within the large bacterial inoculum associated with most pneumonias may be the cause. Acinetobacter species, Stenotrophomonas maltophilia, and Burkholderia cepacia are intrinsically resistant to many of the empirical antibiotic regimens employed (see later in this chapter). VAP caused by these pathogens emerges during treatment of other infections, and resistance is always evident at initial diagnosis. EMPIRICAL THERAPY
Recommended options for empirical therapy are listed in Table 153-9. Treatment should be started once diagnostic specimens have been obtained. The major factor in the selection of agents is the presence of risk factors for MDR pathogens. Choices among the various options listed depend on local patterns of resistance and—a very important factor—the patient’s prior antibiotic exposure.
The majority of patients without risk factors for MDR infection can be treated with a single agent. The major difference from CAP is the markedly lower incidence of atypical pathogens in VAP; the exception is Legionella, which can be a nosocomial pathogen, especially with breakdowns in the treatment of potable water in the hospital. The standard recommendation for patients with risk factors for MDR infection is for three antibiotics: two directed at P. aeruginosa and one at MRSA. The choice of a β-lactam agent provides the greatest variability in coverage, yet the use of the broadest-spectrum agent—a carbapenem, even in an antibiotic combination—still represents inappropriate initial therapy in 10–15% of cases. SPECIFIC TREATMENT
Once an etiologic diagnosis is made, broad-spectrum empirical therapy can be modified to specifically address the known pathogen. For patients with MDR risk factors, antibiotic regimens can be reduced to a single agent in more than one-half of cases and to a two-drug combination in more than one-quarter of cases. Only a minority of cases require a complete course with three drugs. A negative tracheal-aspirate culture or growth below the threshold for quantitative cultures, especially if the sample was obtained before any antibiotic change, strongly suggests that antibiotics should be discontinued. Identification of other confirmed or suspected sites of infection may require ongoing antibiotic therapy, but the spectrum of pathogens (and the corresponding antibiotic choices) may be different from those for VAP. If the CPIS decreases over the first 3 days, antibiotics should be stopped after 8 days. An 8-day course of therapy is just as effective as a 2-week course and is associated with less frequent emergence of antibiotic-resistant strains.
The major controversy regarding specific therapy for VAP concerns the need for ongoing combination treatment of Pseudomonas infection. No randomized controlled trials have demonstrated a benefit of combination therapy with a β-lactam and an aminoglycoside, nor have subgroup analyses in other trials found a survival benefit with such a regimen. The unacceptably high rates of clinical failure and death for VAP caused by P. aeruginosa despite combination therapy (see “Failure to Improve,” later) indicate that better regimens are needed—including, perhaps, aerosolized antibiotics. VAP caused by MRSA is associated with a 40% clinical failure rate when treated with standard-dose vancomycin. One proposed solution is the use of high-dose individualized treatment, although the risk of renal toxicity increases with this strategy. In addition, the MIC of vancomycin has been increasing, and a high percentage of clinical failures occur when the MIC is in the upper range of sensitivity (i.e., 1. 5–2 μg/mL). Linezolid appears to be 15% more efficacious than even adjusted-dose vancomycin and is clearly preferred in patients with renal insufficiency and those infected with high-MIC isolates of MRSA. FAILURE TO IMPROVE
Treatment failure is not uncommon in VAP, especially that caused by MDR pathogens. In addition to the 40% failure rate for MRSA infection treated with vancomycin, VAP due to Pseudomonas has a 50% failure rate, no matter what the regimen. Causes of clinical failure vary with the pathogen(s) and the antibiotic(s). Inappropriate therapy can usually be minimized by use of the recommended triple-drug regimen (Table 153-9). However, the emergence of β-lactam resistance during therapy is an important problem, especially in infection with Pseudomonas and Enterobacter species. Recurrent VAP caused by the same pathogen is possible because the biofilm on endotracheal tubes allows reintroduction of the microorganism. However, studies of VAP caused by Pseudomonas show that approximately half of recurrent cases are caused by a new strain. Inadequate local levels of vancomycin are the likely cause of treatment failure in VAP due to MRSA.
Treatment failure is very difficult to diagnose. Pneumonia due to a new superinfection, the presence of extrapulmonary infection, and drug toxicity must be considered in the differential diagnosis of treatment failure. Serial CPIS calculations appear to track the clinical response accurately, while repeat quantitative cultures may clarify the microbiologic response. A persistently elevated or rising CPIS by day 3 of therapy is likely to indicate treatment failure. The most sensitive component of the CPIS is improvement in oxygenation. COMPLICATIONS
Apart from death, the major complication of VAP is prolongation of mechanical ventilation, with corresponding increases in length of stay in the ICU and in the hospital. In most studies, an additional week of mechanical ventilation resulting from VAP is common. The additional expense of this complication often warrants costly and aggressive efforts at prevention.
In rare cases, some types of necrotizing pneumonia (e.g., that due to P. aeruginosa) result in significant pulmonary hemorrhage. More commonly, necrotizing infections result in the long-term complications of bronchiectasis and parenchymal scarring leading to recurrent pneumonias. The long-term complications of pneumonia are underappreciated. Pneumonia results in a catabolic state in a patient already nutritionally at risk. The muscle loss and general debilitation from an episode of VAP often require prolonged rehabilitation and, in the elderly, commonly result in an inability to return to independent function and the need for nursing home placement. FOLLOW-UP
Clinical improvement, if it occurs, is usually evident within 48–72 h of the initiation of antimicrobial treatment. Because findings on chest radiography often worsen initially during treatment, they are less helpful than clinical criteria as an indicator of clinical response in severe pneumonia. Seriously ill patients with pneumonia often undergo follow-up chest radiography daily, at least until they are being weaned off mechanical ventilation.
TABLE 153-9Empirical Antibiotic Treatment of Health Care–Associated Pneumonia ||Download (.pdf) TABLE 153-9Empirical Antibiotic Treatment of Health Care–Associated Pneumonia
VAP is associated with significant mortality. Crude mortality rates of 50–70% have been reported, but the real issue is attributable mortality. Many patients with VAP have underlying diseases that would result in death even if VAP did not occur. Attributable mortality exceeded 25% in one matched-cohort study, while more recent studies have suggested much lower rates. Patients who develop VAP are at least twice as likely to die as those who do not. Some of the variability in VAP mortality rates is clearly related to the type of patient and ICU studied. VAP in trauma patients is not associated with attributable mortality, possibly because many of the patients were otherwise healthy before being injured. However, the causative pathogen also plays a major role. Generally, MDR pathogens are associated with significantly greater attributable mortality than non-MDR pathogens. Pneumonia caused by some pathogens (e.g., S. maltophilia) is simply a marker for a patient whose immune system is so compromised that death is almost inevitable.
(Table 153-7) Because of the significance of the endotracheal tube as a risk factor for VAP, the most important preventive intervention is to avoid endotracheal intubation or minimize its duration. Successful use of noninvasive ventilation via a nasal or full-face mask avoids many of the problems associated with endotracheal tubes. Strategies that minimize the duration of ventilation through daily holding of sedation and formal weaning protocols also have been highly effective in preventing VAP.
Unfortunately, a tradeoff in risks is sometimes required. Aggressive attempts to extubate early may result in reintubation(s) and increase aspiration, posing a risk of VAP. Heavy continuous sedation increases the risk, but self-extubation because of insufficient sedation also is a risk. The tradeoffs also apply to antibiotic therapy. Short-course antibiotic prophylaxis can decrease the risk of VAP in comatose patients requiring intubation, and data suggest that antibiotics decrease VAP rates in general. However, the major benefit appears to be a decrease in the incidence of early-onset VAP, which is usually caused by the less pathogenic non-MDR microorganisms. Conversely, prolonged courses of antibiotics consistently increase the risk of VAP caused by the more lethal MDR pathogens. Despite its virulence and associated mortality, VAP caused by Pseudomonas is rare among patients who have not recently received antibiotics.
Minimizing the amount of microaspiration around the endotracheal tube cuff also is a strategy for avoidance of VAP. Simply elevating the head of the bed (at least 30° above horizontal but preferably 45°) decreases VAP rates. Specially modified endotracheal tubes that allow removal of the secretions pooled above the cuff also may prevent VAP. The risk-to-benefit ratio of transporting the patient outside the ICU for diagnostic tests or procedures should be carefully considered, since VAP rates are increased among transported patients.
Emphasis on the avoidance of agents that raise gastric pH and on oropharyngeal decontamination has been diminished by the equivocal and conflicting results of recent clinical trials. The role in the pathogenesis of VAP that is played by the overgrowth of bacterial components of the bowel flora in the stomach also has been downplayed. MRSA and the nonfermenters P. aeruginosa and Acinetobacter species are not normally part of the bowel flora but reside primarily in the nose and on the skin, respectively. Therefore, emphasis on controlling overgrowth of the bowel flora may be relevant only in certain populations, such as liver transplant recipients and patients who have undergone other major intraabdominal procedures or who have bowel obstruction.
In outbreaks of VAP due to specific pathogens, the possibility of a breakdown in infection control measures (particularly contamination of reusable equipment) should be investigated. Even high rates of pathogens that are already common in a particular ICU may be a result of cross-infection. Education and reminders of the need for consistent hand washing and other infection-control practices can minimize this risk.
While significantly less well studied than VAP, HAP in nonintubated patients—both inside and outside the ICU—is similar to VAP. The main differences are the higher frequency of non-MDR pathogens and the better underlying host immunity in nonintubated patients. The lower frequency of MDR pathogens allows monotherapy in a larger proportion of cases of HAP than of VAP.
The only pathogens that may be more common in the non-VAP population are anaerobes. The greater risk of macroaspiration by nonintubated patients and the lower oxygen tensions in the lower respiratory tract of these patients increase the likelihood of a role for anaerobes. While more common in patients with HAP, anaerobes are usually only contributors to polymicrobial pneumonias except in patients with large-volume aspiration or in the setting of bowel obstruction/ileus. As in the management of CAP, specific therapy targeting anaerobes probably is not indicated (unless gross aspiration is a concern) since many of the recommended antibiotics are active against anaerobes.
Diagnosis is even more difficult for HAP in the nonintubated patient than for VAP. Lower respiratory tract samples appropriate for culture are considerably more difficult to obtain from nonintubated patients. Many of the underlying diseases that predispose a patient to HAP are also associated with an inability to cough adequately. Since blood cultures are infrequently positive (<15% of cases), the majority of patients with HAP do not have culture data on which antibiotic modifications can be based. Therefore, de-escalation of therapy is less likely in patients with risk factors for MDR pathogens. Despite these difficulties, the better host defenses in non-ICU patients result in lower mortality rates than are documented for VAP. In addition, the risk of antibiotic failure is lower in HAP.