Pneumonia

Definition

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, hospital-acquired, or ventilator-associated. Over the last decade or two, however, patients presenting to the hospital have often been found to be infected with multidrug-resistant (MDR) pathogens previously associated with hospital-acquired pneumonia. 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 revised classification system in which infection is categorized as either community-acquired pneumonia (CAP) or health care–associated pneumonia (HCAP), with subcategories of HCAP including hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). The conditions associated with HCAP and the likely pathogens are listed in Table 251-1.

Table 251-1 Clinical Conditions Associated with and Likely Pathogens in Health Care–Associated Pneumonia

Pathogen Condition MRSA Pseudomonas aeruginosa Acinetobacter spp. MDR Enterobacteriaceae Hospitalization for 48 h X X X X Hospitalization for 2 days in prior 3 months X X X X Nursing home or extended-care facility residence X X X X Antibiotic therapy in preceding 3 months X X Chronic dialysis X Home infusion therapy X Home wound care X Family member with MDR infection X X

Note: MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus. Although the new classification system has been helpful in designing empirical antibiotic strategies, it is not without disadvantages. For instance, not all MDR pathogens are associated with all risk factors (Table 251-1). Therefore, this system represents 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 with dementia who 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. Pathophysiology 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 catch larger inhaled particles before they reach the lower respiratory tract, and the branching architecture of the tracheobronchial tree traps particles 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 the 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 local proteins (e.g., surfactant proteins A and D) that have intrinsic opsonizing properties or antibacterial or antiviral activity. Once engulfed, the pathogens—even if they are not killed by macrophages—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 the proliferation of microorganisms, triggers the clinical syndrome of pneumonia. The release of inflammatory mediators, such as interleukin (IL) 1 and tumor necrosis factor (TNF), results in fever. Chemokines, such as IL-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 (ARDS), 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 hypoxic 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 (SIRS) 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 the patient's death. Pathology 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 it is so rapidly followed by a red hepatization phase. The presence of erythrocytes in the cellular intraalveolar exudate gives this second stage its name, but neutrophils are also present and are important from the standpoint of host defense. Bacteria are occasionally seen in cultures of alveolar 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 is 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 pneumococcal pneumonia and may not apply to pneumonias 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. Etiology The extensive list of potential etiologic agents in CAP includes bacteria, fungi, viruses, and protozoa. Newly identified pathogens include hantaviruses, metapneumoviruses, the coronavirus responsible for the severe acute respiratory syndrome (SARS), and community-acquired strains of methicillin-resistant Staphylococcus aureus (MRSA). Most cases of CAP, however, are caused by relatively few pathogens (Table 251-2). Although Streptococcus pneumoniae is most common, other organisms must also be considered in light of the patient's risk factors and severity of illness. In most cases, it is most useful to think of the potential causes as either "typical" bacterial pathogens or "atypical" organisms. 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, Chlamydophila pneumoniae, and Legionella spp. as well as respiratory viruses such as influenza viruses, adenoviruses, and respiratory syncytial viruses (RSVs). Data suggest that a virus may be responsible in up to 18% of cases of CAP that require admission to the hospital. The atypical organisms cannot be cultured on standard media, nor can they be seen on Gram's stain. The frequency and importance of atypical pathogens such as M. pneumoniae and C. pneumoniae in outpatients and Legionella in inpatients have significant implications for therapy. These organisms are intrinsically resistant to all -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 often includes a combination of typical and atypical pathogens. Table 251-2 Microbial 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 Chlamydophila pneumoniae Legionella spp. C. pneumoniae H. influenzae Gram-negative bacilli Respiratory virusesa Legionella spp. H. influenzae Respiratory virusesa Note: Pathogens are listed in descending order of frequency. ICU, intensive care unit. aInfluenza A and B viruses, adenoviruses, respiratory syncytial viruses, parainfluenza viruses. Anaerobes play a significant role only when an episode of aspiration has occurred days to weeks before presentation for 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 significant empyemas or parapneumonic effusions. S. aureus pneumonia is well known to complicate influenza infection. Recently, however, MRSA strains have been reported as primary causes 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. These novel community-acquired MRSA (CA-MRSA) strains have infected healthy individuals who have had no association with health care. Unfortunately, despite a careful history and physical examination as well as routine radiographic studies, it is usually impossible to predict the pathogen in a case of CAP with any degree of certainty; in more than half of cases, a specific etiology is never determined. Nevertheless, it is important to consider epidemiologic and risk factors that might suggest certain pathogens (Table 251-3). Table 251-3 Epidemiologic 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, Chlamydophila 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 Chlamydophila psittaci Exposure to rabbits Francisella tularensis Exposure to sheep, goats, parturient cats Coxiella burnetii Note: CA-MRSA, community-acquired methicillin-resistant Staphylococcus aureus; COPD, chronic obstructive pulmonary disease. Epidemiology In the United States, ~80% of the 4 million CAP cases that occur annually are treated on an outpatient basis, and ~20% are treated in the hospital. CAP results in more than 600,000 hospitalizations, 64 million days of restricted activity, and 45,000 deaths annually. The overall yearly cost associated with CAP is estimated at $9–10 billion (U.S.). The incidence rates are highest at the extremes of age. Although the overall annual figure in the United States is 12 cases per 1000 persons, the figure is 12–18 per 1000 among children <4>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 versus 60–69 years. 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 infection is more likely in Native Americans, homeless youths, men who have sex with men, prison inmates, military recruits, children in day-care centers, and athletes such as wrestlers. The Enterobacteriaceae tend to affect 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 may also infect these patients as well as those with severe structural lung 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.) Clinical Manifestations CAP can vary from indolent to fulminant in presentation and from mild to fatal in severity. The various signs and symptoms, which depend on the progression and severity of the infection, include both constitutional findings and manifestations limited to the lung and its associated structures. In light of the pathobiology of the disease, many of the findings are to be expected. The patient is frequently febrile, with a tachycardic response, and may have chills and/or sweats and cough that is either nonproductive or productive of mucoid, purulent, or blood-tinged sputum. In accordance with the severity of infection, 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 who have septic shock secondary to CAP are hypotensive and may have evidence of organ failure. Diagnosis When confronted with possible CAP, the physician must ask two questions: Is this pneumonia, and, if so, what is the etiology? The former question is typically answered by clinical and radiographic methods, whereas the latter requires the aid of laboratory techniques. Clinical Diagnosis The differential diagnosis includes both infectious and noninfectious entities such as acute bronchitis, acute exacerbations of chronic bronchitis, heart failure, pulmonary embolism, 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 radiation. Epidemiologic clues, such as recent travel to areas with known endemic pathogens, may alert the physician to specific possibilities (Table 251-3). 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 help differentiate CAP from other conditions. Radiographic findings serve as a baseline and 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 is rarely necessary but may be of value in a patient with suspected postobstructive pneumonia caused by a tumor or foreign body. For cases managed on an outpatient basis, the clinical and radiologic assessment is usually all that is done before treatment is started since most laboratory test results are not available soon enough to influence initial management. In certain cases, however (e.g., influenza virus infection), the availability of rapid point-of-care diagnostic tests and access to specific drugs for treatment and prevention can be very important. Etiologic Diagnosis The etiology of pneumonia usually cannot be determined on the basis of clinical presentation; instead, the physician must rely upon the laboratory for support. Except for the 2% of CAP patients who are admitted to the intensive care unit (ICU), no data exist to show that treatment directed at a specific pathogen is statistically superior to empirical therapy. The benefits 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, which decreases antibiotic selection pressure and may lessen 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 help to 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 src="http://www.blogger.com/251_files/lesserorequal.gif">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, which can interfere with results, at the time a sample is obtained. The 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 should be sent to the microbiology laboratory as soon as possible. Since the etiologies in severe CAP are somewhat different from those in milder disease (Table 251-2), 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 may be useful as well. For suspected tuberculosis or fungal infection, specific stains are available. Cultures of pleural fluid obtained from effusions >1 cm in height on a lateral decubitus chest radiograph may also be helpful. Blood Cultures The yield from blood cultures, even those obtained 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 a switch from a broader-spectrum regimen (e.g., a fluoroquinolone or -lactam plus a macrolide) to penicillin 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, or complement deficiencies; chronic liver disease; or severe CAP—should have blood cultured. Antigen Tests Two commercially available tests detect pneumococcal and certain Legionella antigens in urine. The test for Legionella pneumophila detects only serogroup 1, but this serogroup accounts for most community-acquired cases of Legionnaires' disease. The sensitivity and specificity of the Legionella urine antigen test are as high as 90% and 99%, respectively. The pneumococcal urine antigen test is also quite sensitive and specific (80% and >90%, respectively). Although false-positive results can be obtained with samples from colonized children, the test is generally reliable. Both tests can detect antigen even after the initiation of appropriate antibiotic therapy and after weeks of illness. Other antigen tests include a rapid test for influenza virus and direct fluorescent antibody tests for influenza virus and RSV, although the test for RSV is only poorly sensitive. Polymerase Chain Reaction Polymerase chain reaction (PCR) tests are available for a number of pathogens, including L. pneumophila and mycobacteria. In addition, a multiplex PCR can detect the nucleic acid of Legionella spp., M. pneumoniae, and C. pneumoniae. However, the use of these PCR assays is generally limited to research studies. Serology 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 some typical but relatively 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. Community-Acquired Pneumonia: Treatment Site of Care The decision to hospitalize a patient with CAP must take into consideration diminishing health care resources and rising costs of treatment. The cost of inpatient management exceeds that of outpatient treatment by a factor of 20 and accounts for most CAP-related expenditures. 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, may minimize unnecessary hospital admissions and help to identify patients who will benefit from hospital care. 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%. Clinical trials have demonstrated that routine use of the PSI results in lower admission rates for class 1 and class 2 patients. Patients in classes 4 and 5 should be admitted to the hospital, while those in class 3 should 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 (65). 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 admission to an ICU. At present, it is difficult to say which assessment tool is superior. The PSI is less practical in a busy emergency-room setting because of the need to assess 20 variables. While the CURB-65 criteria are easily remembered, they have not been studied as extensively. 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. 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. Pneumococcal strains are classified as sensitive to penicillin if the minimal inhibitory concentration (MIC) is 0.06 g/mL, as intermediate if the MIC is 0.1–1.0 g/mL, and as resistant if the MIC is 2 g/mL. Strains resistant to drugs from three or more antimicrobial classes with different mechanisms of action are considered MDR isolates. Pneumococcal resistance to -lactam drugs is due solely to the presence of low-affinity penicillin-binding proteins. The propensity for pneumococcal resistance to penicillin to be associated with reduced susceptibility to other drugs, such as macrolides, tetracyclines, and trimethoprim-sulfamethoxazole (TMP-SMX), is of concern. In the United States, 58.9% of penicillin-resistant pneumococcal isolates from blood cultures are also resistant to macrolides. Penicillin is an appropriate agent for the treatment of pneumococcal infection caused by strains with MICs of 1 g/mL. For infections caused by pneumococcal strains with penicillin MICs of 2–4 g/mL, the data are conflicting; some studies suggest no increase in treatment failure with penicillin, while others suggest increased rates of death or complications. For strains of S. pneumoniae with intermediate levels of resistance, higher doses of the drug should be used. Risk factors for drug-resistant pneumococcal infection include recent antimicrobial therapy, an age of <2>65 years, attendance at day-care centers, recent hospitalization, and HIV infection. Fortunately, resistance to penicillin appears to be reaching a plateau. In contrast, resistance to macrolides is increasing through several mechanisms, including target-site modification and the presence of an efflux pump. Target-site modification is caused by ribosomal methylation in 23S rRNA encoded by the ermB gene and results in resistance to macrolides, lincosamides, and streptogramin B–type antibiotics. This MLSB phenotype is associated with high-level resistance, with typical MICs of 64 g/mL. The efflux mechanism encoded by the mef gene (M phenotype) is usually associated with low-level resistance (MICs, 1–32 g/mL). These two mechanisms account for ~45% and ~65%, respectively, of resistant pneumococcal isolates in the United States. Some pneumococcal isolates with both the erm and mef genes have been identified, but the exact significance of this finding is unknown. High-level resistance to macrolides is more common in Europe, whereas lower-level resistance seems to predominate in North America. Although clinical failures with macrolides have been reported, many experts think that these drugs still have a role to play in the management of pneumococcal pneumonia 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); changes in these two sites usually result from mutations in the gyrA and parC genes, respectively. The increasing number of pneumococcal isolates that, although susceptible to fluoroquinolones, already have a mutation in one target site is of concern. Such organisms may be more likely to undergo a second step mutation that will render them fully resistant to fluoroquinolones. In addition, an efflux pump may play a role in pneumococcal resistance to fluoroquinolones. CA-MRSA CAP due to MRSA may be caused by infection with the classic hospital-acquired strains or with 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, although classified as HAP in the past, would now be classified as HCAP. In some hospitals, CA-MRSA strains are displacing the classic hospital-acquired strains—a trend suggesting that the newer strains may be more robust. Methicillin resistance in S. aureus is determined by the mecA gene, which encodes for resistance to all -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 TMP-SMX, clindamycin, and tetracycline in addition to vancomycin and linezolid. However, CA-MRSA strains may 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 (see Chap. 143). Fluoroquinolone resistance among isolates of Escherichia coli from the community appears to be increasing. Enterobacter spp. 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 -lactamases (ESBLs) 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 physician rarely knows the etiology of CAP at the outset of treatment, initial therapy is usually empirical and is designed to cover the most likely pathogens (Table 251-4). In all cases, antibiotic treatment should be initiated as expeditiously as possible. Table 251-4 Empirical Antibiotic Treatment of Community-Acquired Pneumonia Outpatients 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 od)] or Doxycycline (100 mg PO bid) Comorbidities or antibiotics in past 3 months: select an alternative from a different class A respiratory fluoroquinolone [moxifloxacin (400 mg PO od), gemifloxacin (320 mg PO od), levofloxacin (750 mg PO od)] or A -lactam [preferred: high-dose amoxicillin (1 g tid) or amoxicillin/clavulanate (2 g bid); alternatives: ceftriaxone (1–2 g IV od), cefpodoxime (200 mg PO bid), cefuroxime (500 mg PO bid)] plus a macrolidea 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 [moxifloxacin (400 mg PO or IV od), gemifloxacin (320 mg PO od), levofloxacin (750 mg PO or IV od)] A -lactamc [cefotaxime (1–2 g IV q8h), ceftriaxone (1–2 g IV od), ampicillin (1–2 g IV q4–6h), ertapenem (1 g IV od in selected patients)] plus a macrolided [oral clarithromycin or azithromycin (as listed above for previously healthy patients) or IV azithromycin (1 g once, then 500 mg od)] Inpatients, ICU A -lactame [cefotaxime (1–2 g IV q8h), ceftriaxone (2 g IV od), ampicillin-sulbactam (2 g IV q8h)] plus Azithromycin or a fluoroquinolone (as listed above for inpatients, non-ICU) Special concerns If Pseudomonas is a consideration An antipneumococcal, antipseudomonal -lactam [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 od) The above -lactams plus an aminoglycoside [amikacin (15 mg/kg od) or tobramycin (1.7 mg/kg od) and azithromycin] The above -lactamsf plus an aminoglycoside plus an antipneumococcal fluoroquinolone If CA-MRSA is a consideration Add linezolid (600 mg IV q12h) or vancomycin (1 g IV q12h) Note: CA-MRSA, community-acquired methicillin-resistant Staphylococcus aureus; ICU, intensive care unit. aDoxycycline (100 mg PO bid) is an alternative to the macrolide. bMICs of >16 g/mL in 25% of isolates. cA respiratory fluoroquinolone should be used for penicillin-allergic patients. dDoxycycline (100 mg IV q12h) is an alternative to the macrolide. eFor penicillin-allergic patients, use a respiratory fluoroquinolone and aztreonam (2 g IV q8h). fFor penicillin-allergic patients, substitute aztreonam. The CAP treatment guidelines in the United States (summarized in Table 251-4) represent joint statements from the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS); the Canadian guidelines come from the Canadian Infectious Disease Society and the Canadian Thoracic Society. In 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 from almost 13,000 patients >65 years of age. Atypical pathogen coverage provided by a macrolide or a fluoroquinolone has been associated with a significant reduction in mortality rates compared with those for -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 macrolide- or fluoroquinolone-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 251-4). Telithromycin, a ketolide derived from the macrolide class, differs from the macrolides in that it binds to bacteria more avidly and at two sites rather than one. This drug is active against pneumococci resistant to penicillins, macrolides, and fluoroquinolones. Its future role in the outpatient management of CAP will depend on the evaluation of its safety by the U.S. Food and Drug Administration. 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 -lactam or a fluoroquinolone, should therapy be switched to penicillin? Penicillin alone would not be effective in the potential 15% of cases with atypical co-infection. No standard approach exists. Some experts would argue that pneumococcal coverage by a switch to penicillin is appropriate, while others would opt for continued coverage of both the pneumococcus and atypical pathogens. One compromise would be to continue atypical coverage with either a macrolide or a fluoroquinolone for a few more days and then to complete the treatment course with penicillin alone. In all cases, the individual patient and the various risk factors must be considered. Management of bacteremic pneumococcal pneumonia is also controversial. Data from nonrandomized studies suggest that combination therapy (e.g., with a macrolide and a -lactam) is associated with a lower mortality rate than monotherapy, particularly in severely ill patients. The exact reason is unknown, but explanations include possible atypical co-infection or the immunomodulatory effects of the macrolides. For patients with CAP who are admitted to the ICU, the risk of infection with P. aeruginosa or CA-MRSA is increased, and coverage should be considered when a patient has risk factors or a Gram's stain suggestive of these pathogens (Table 251-4). The main risk factors for P. aeruginosa infection are structural lung disease (e.g., bronchiectasis) and recent treatment with antibiotics or glucocorticoids. If CA-MRSA infection is suspected, either linezolid or vancomycin should be added to the initial empirical regimen. 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 recently generated considerable interest. Patients have usually been treated for 10–14 days, but recent studies with fluoroquinolones and telithromycin suggest that a 5-day course is sufficient for otherwise uncomplicated CAP. A longer course is required for patients with bacteremia, metastatic infection, or infection with a particularly virulent pathogen, such as P. aeruginosa or CA-MRSA. Longer-term therapy should also be considered if initial treatment was ineffective and in most cases of severe CAP. Data from studies with azithromycin, which suggest 3–5 days of treatment for outpatient-managed CAP, cannot be extrapolated to other drugs because of the extremely long half-life of azithromycin. Patients may be discharged from the hospital once they are clinically stable and have no active medical problems requiring ongoing hospital care. The site of residence after discharge (in a nursing home, at home with family, at home alone) is an important consideration, particularly for elderly patients. Prognosis 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 the deaths directly attributable to pneumonia. Prevention The main preventive measure is vaccination. The recommendations of the Advisory Committee on Immunization Practices should be followed for influenza and pneumococcal vaccines. 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. Because of an increased risk of pneumococcal infection, even among patients without obstructive lung disease, smokers should be strongly encouraged to stop smoking.