Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

85. Lower Respiratory Tract Infections

Martha G. Blackford, Mark L. Glover, and Michael D. Reed


KEY CONCEPTS

 Images Respiratory infections remain the major cause of morbidity from acute illness in the United States and likely represent the most common reasons why patients seek medical attention.

 Images The majority of pulmonary infections follow colonization of the upper respiratory tract with potential pathogens, whereas microbes less commonly gain access to the lungs via the blood from an extrapulmonary source or by inhalation of infected aerosol particles. The competency of a patient’s immune status is an important factor influencing the susceptibility to infection, etiologic cause, and disease severity.

 Images An appropriate treatment regimen for the patient with uncomplicated lower respiratory tract infection can be established by evaluating the patient history, physical examination, chest radiograph, and properly collected sputum for culture and interpreted in light of current knowledge of the most common lung pathogens and their antibiotic susceptibility patterns within the community.

 Images Acute bronchitis is caused most commonly by respiratory viruses and almost always is self-limiting. Therapy targets associated symptoms, such as lethargy, malaise, or fever (ibuprofen or acetaminophen), and fluids for rehydration. Routine use of antibiotics should be avoided and medication to suppress cough is rarely indicated.

 Images Chronic bronchitis is caused by several interacting factors, including inhalation of noxious agents (most prominent are cigarette smoke and exposure to occupational dusts, fumes, and environmental pollution) and host factors including genetic factors and bacterial (and possibly viral) infections. The hallmark of this disease is a chronic cough, excessive sputum production, and expectoration with persistent presence of microorganisms in the patient’s sputum.

 Images Treatment of acute exacerbations of chronic bronchitis includes attempts to mobilize and enhance sputum expectoration (chest physiotherapy, humidification of inspired air), oxygen if needed, aerosolized bronchodilators (albuterol) in select patients with demonstrated benefit, and antibiotics.

 Images Respiratory syncytial virus is the most common cause of acute bronchiolitis, an infection that mostly affects infants during their first year of life. In the well infant, bronchiolitis usually is a self-limiting viral illness.

 Images The most prominent pathogen causing community-acquired pneumonia in otherwise healthy adults is S. pneumoniae, whereas the most common pathogens causing hospital-acquired and healthcare-associated pneumonia are Staphylococcus aureus and gram-negative aerobic bacilli. Anaerobic bacteria are the most common etiologic agents in pneumonia that follows aspiration of gastric or oropharyngeal contents.

 Images Treatment of community-acquired pneumonia may consist of humidified oxygen for hypoxemia, bronchodilators (albuterol) when bronchospasm is present, rehydration fluids, and chest physiotherapy for marked accumulation of retained respiratory secretions. Antibiotic regimens should be selected based on presumed causative pathogens and pulmonary distribution characteristics and should be adjusted to provide optimal activity against pathogens identified by culture (sputum or blood).

 Images Treatment of nosocomial pneumonia requires aggressive therapy with careful consideration of the dominance and susceptibility patterns of the pathogens present within the institution.


Images Respiratory tract infections remain the major cause of morbidity from acute illness in the United States and most likely represent the single most common reason patients seek medical attention. This chapter focuses on bacterial and viral infections involving the lower respiratory tract, which includes the tracheobronchial tree and lung parenchyma.

Images The respiratory tract has an elaborate system of host defenses, including humoral immunity, cellular immunity, and anatomic mechanisms.1 When functioning properly, the host defenses of the respiratory tract are markedly effective in protecting against pathogen invasion and removing potentially infectious agents from the lungs. For the most part, infections in the lower respiratory tract occur only when these defense mechanisms are impaired, as in cases of dysgammaglobulinemia or compromised ciliary function, such as that caused by the chronic inflammation accompanying cigarette smoking. In addition, local defenses may be overwhelmed when a particularly virulent microorganism or excessive inoculum invades lung parenchyma. The majority of pulmonary infections follow colonization of the upper respiratory tract with potential pathogens, which, after achieving sufficiently high concentrations, gain access to the lung via aspiration of oropharyngeal secretions. Less commonly, microbes enter the lung via the blood from an extrapulmonary source or by inhalation of infected aerosolized particles. The specific type of pulmonary infection caused by an invading microorganism is determined by a variety of host factors, including age, anatomic features of the airway, and specific characteristics of the infecting agent.

The most common infections involving the lower respiratory tract are bronchitis, bronchiolitis, and pneumonia. Lower respiratory tract infections in children and adults most commonly result from either viral or bacterial invasion of lung parenchyma. The diagnosis of viral infections rests primarily on the recognition of a characteristic constellation of clinical signs and symptoms. Because treatment is largely supportive, only occasionally does the diagnosis require laboratory confirmation; this is achieved through serologic tests or identification of the organism by culture or antigen detection in respiratory secretions.2 Laboratory techniques using polymerase chain reaction (PCR), real-time PCR, microarrays, and multiplex ligation-dependent probe amplification, to name a few, have emerged as a means to identify specific pathogens rapidly and accurately.3

In contrast, because bacterial pneumonia usually necessitates expedient, effective, and specific antibiotic therapy, its management depends, in large part, on an understanding of the risk factors for acquiring pneumonia, predominant pathogens within the community, and, if necessary, isolation of the etiologic agent by culture from lung tissue or secretions.47 The pharynx is colonized with many organisms that can cause pneumonia; therefore, culture of expectorated sputum can be misleading unless the specimen is examined to ensure that it has originated from the lower respiratory tract. The Gram stain provides the easiest method for distinguishing lower from upper respiratory tract secretions; moreover, through determination of the shape and color of the bacteria, the Gram stain frequently narrows the microbiologic differential diagnosis sufficiently to allow accurate initial therapy. Scanned under low-power microscopy, Gram-stained expectorated upper respiratory tract secretions contain many irregularly shaped epithelial cells with little evidence of inflammation and may not reflect the pathogen. In contrast, a lower-tract specimen from a patient with bacterial pneumonia usually contains multiple neutrophils per high-powered field and a single or predominant bacterial species. Culture of specimens confirmed to originate from the lower tract by Gram stain provides valuable diagnostic information for the majority of patients with bacterial pneumonia. In addition, pneumonia promotes the release of inflammatory mediators and acute-phase proteins such as C-reactive protein, which is significantly elevated in serum in the presence of respiratory tract infections.8

Images An appropriate treatment regimen for the patient with an uncomplicated lower respiratory tract infection usually can be established by history, physical examination, chest radiograph, and properly collected sputum cultures interpreted in light of the most common lung pathogens and their antibiotic susceptibility patterns within the community.2,4,6,9 More sophisticated or invasive diagnostic methods (e.g., computed tomography, bronchoscopy, and lung biopsy)2 are reserved for severely ill patients who are unable to expectorate sputum or who are not responding to empirical therapy or for pulmonary infections occurring in immunocompromised patients.

BRONCHITIS

Bronchitis and bronchiolitis are inflammatory conditions of the large and small elements, respectively, of the tracheobronchial tree. The inflammatory process does not extend to the alveoli. Bronchitis frequently is classified as acute or chronic. Acute bronchitis occurs in individuals of all ages, whereas chronic bronchitis primarily affects adults. Bronchiolitis is a disease of infancy.

Acute Bronchitis

Epidemiology and Etiology

Acute bronchitis occurs most commonly during the winter months, following a pattern similar to those of other acute respiratory tract infections. Cold, damp climates and the presence of high concentrations of irritating substances (e.g., air pollution, cigarette smoke) may precipitate attacks.

Images Respiratory viruses are by far the most common infectious agents associated with acute bronchitis.10 The common cold viruses (rhinovirus and coronavirus) and lower respiratory tract pathogens (influenza virus and adenovirus) account for the majority of cases. Wider use of reverse transcriptase PCR diagnostic evaluations has identified respiratory viral pathogens not previously described as etiologic agents in acute bronchitis and bronchiolitis including the human metapneumovirus and bocavirus.11 In children, similar pathogens are observed, with the addition of the parainfluenza viruses. Although the true incidence remains to be defined, Mycoplasma pneumoniaeappears to be a frequent cause of acute bronchitis. Additionally, Chlamydophila pneumoniae (also referred to as Chlamydophila)12 and B. pertussis13 (agent responsible for whooping cough) have been associated with acute respiratory tract infections. Although a variety of bacteria, including S. pneumoniaeStreptococcus species, Staphylococcusspecies, and Haemophilus species, may be isolated from throat or sputum culture, these organisms probably represent contamination by normal flora of the upper respiratory tract rather than true pathogens. Although a primary bacterial etiology for acute bronchitis appears rare, secondary bacterial infection may be involved.

Pathogenesis

Images Because acute bronchitis is primarily a self-limiting illness and rarely a cause of death, few data describing the pathology are available. In general, infection of the trachea and bronchi yields hyperemic and edematous mucous membranes with an increase in bronchial secretions. Destruction of respiratory epithelium can range from mild to extensive and may affect bronchial mucociliary function. In addition, the increase in desquamated epithelial cells and bronchial secretions, which can become thick and tenacious, further impairs mucociliary activity. The probability of permanent damage to the airways as a result of acute bronchitis remains unclear but appears unlikely. However, epidemiologic evaluations support the belief that recurrent acute respiratory infections may be associated with increased airway hyperreactivity and possibly the pathogenesis of asthma or chronic obstructive pulmonary disease (COPD).

Clinical Presentation

Acute bronchitis usually begins as an upper respiratory infection with nonspecific complaints.10,14 Cough is the hallmark of acute bronchitis and occurs early. The onset of cough may be insidious or abrupt, and the symptoms persist despite resolution of nasal or nasopharyngeal complaints; cough may persist for up to 3 or more weeks. Frequently, the cough initially is nonproductive but then progresses, yielding mucopurulent sputum. In older children and adults, the sputum is raised and expectorated; in the young child, sputum often is swallowed and can result in gagging and vomiting. Substantial discomfort may result from the coughing. Dyspnea, cyanosis, or signs of airway obstruction are observed rarely unless the patient has underlying pulmonary disease, such as emphysema or COPD. Fever, when present, rarely exceeds 39°C (102.2°F) and appears most commonly with adenovirus, influenza virus, and M. pneumoniae infections. The diagnosis typically is made on the basis of a characteristic history and physical examination. Bacterial cultures of expectorated sputum generally are of limited use because of the inability to avoid normal nasopharyngeal flora by the sampling technique. In routine cases, viral cultures are unnecessary and frequently unavailable. Viral antigen detection tests, developed to identify respiratory viral antigens from nasal secretions rapidly, can be obtained in many hospital laboratories and in some practice settings when a specific diagnosis is necessary for clinical or epidemiologic reasons. Cultures, serologic or PCR diagnosis of M. pneumoniae, and culture, direct fluorescent antibody detection, or PCR for B. pertussis should be obtained in prolonged or severe cases when epidemiologic considerations would suggest their involvement.

TREATMENT

Desired Outcome

In the absence of a complicating bacterial superinfection, acute bronchitis almost always is self-limiting. The goals of therapy are to provide comfort to the patient and, in the unusually severe case, to treat associated dehydration and respiratory compromise.10

General Approach to Treatment

Images Treatment of acute bronchitis is symptomatic and supportive in nature. Reassurance and antipyretics frequently are all that are needed. Bedrest for comfort may be instituted as desired. Patients should be encouraged to drink fluids to prevent dehydration and possibly to decrease the viscosity of respiratory secretions. Mist therapy (use of a vaporizer) may promote the thinning and loosening of respiratory secretions.

Pharmacologic Therapy

Mild analgesic–antipyretic therapy often is helpful in relieving the associated lethargy, malaise, and fever. Aspirin or acetaminophen (650 mg in adults or 10 to 15 mg/kg per dose in children; maximum daily adult dose <4 g and pediatric dose 60 mg/kg) or ibuprofen (200 to 800 mg in adults or 10 mg/kg per dose in children; maximum daily adult dose 3.2 g and pediatric dose 40 mg/kg) should be administered every 4 to 6 hours. In children, aspirin should be avoided and acetaminophen used as the preferred agent because of the possible association between aspirin use and the development of Reye’s syndrome.15

Use of ibuprofen as an antipyretic has increased. The drug’s antipyretic efficacy appears identical to that of aspirin or acetaminophen, although its duration of antipyretic effect may be slightly longer (e.g., 3 to 4 hours for aspirin and acetaminophen vs. 5 to 6 hours for ibuprofen). Caution should be exercised in the administration of ibuprofen for patients younger than 6 months, elderly patients, and individuals with poor renal function. Aspirin and ibuprofen inhibit prostaglandin synthesis and may adversely influence renal function in these predisposed patient populations.

Patients may present with mild to moderate wheezing. In otherwise healthy patients, no meaningful benefits have been described with the use of oral or aerosolized β2-receptor agonists and/or oral or aerosolized corticosteroids. A Cochrane review showed limited benefit of β2-receptor agonists in both pediatric and adult patients compared with the side effects; however, in adults with airflow obstruction there was a trend toward improvement.16 Some clinicians, despite no data, may initiate a brief trial (e.g., ~5 to 7 days) of oral or inhaled corticosteroid for patients with persistent (>14 to 20 days), troublesome cough. Despite several studies, none support the use of mucolytic agents.

Patients suffering from acute bronchitis frequently medicate themselves with nonprescription cough and cold remedies containing various combinations of antihistamines, sympathomimetics, and antitussives despite the lack of definitive evidence supporting their effectiveness. In fact, the tendency of these agents to dehydrate bronchial secretions could aggravate and prolong the recovery process. Although not recommended for routine use, persistent, mild cough, which may be bothersome, can be treated with dextromethorphan; more severe coughs may require intermittent codeine or other similar agents.10,14 In severe cases, the cough may be persistent enough to disrupt sleep, and use of a mild sedative–hypnotic, concomitantly with a cough suppressant (e.g., codeine), may be desirable. However, antitussives should be used cautiously when the cough is productive. The primary or supplemental use of expectorants is questionable because their clinical effectiveness has not been well established.

Routine use of antibiotics for treatment of acute bronchitis should be discouraged due to limited benefit.10,17 In previously healthy patients who exhibit persistent fever or respiratory symptoms for more than 4 to 6 days or for predisposed patients (e.g., elderly, immunocompromised), the possibility of a concurrent bacterial infection should be suspected. When possible, antibiotic therapy should be directed toward anticipated respiratory pathogen(s) (i.e., S. pneumoniae). M. pneumoniae, if suspected by history or if confirmed by culture serology or PCR, can be treated with azithromycin. Alternatively and empirically, a fluoroquinolone antibiotic with activity against these suspected pathogens (e.g., levofloxacin) can be used. During known epidemics involving the influenza A virus, amantadine or rimantadine may be effective in minimizing associated symptoms if administered early in the course of the disease, although treatment with adamantanes is no longer recommended by the Centers for Disease Control and Prevention (CDC) due to increasing influenza resistance to these two agents.18 The neuraminidase inhibitors (e.g., zanamivir and oseltamivir) are active against both influenza A and B viral infections and may reduce the severity and duration of the influenza episode if administered promptly during the onset of the viral infection and are the preferred treatment (see Chap. 87).19,20 Unfortunately, the incidence of influenza virus resistance to available antiviral drugs is increasing.18,21

Chronic Bronchitis

Epidemiology and Etiology

Chronic bronchitis, a component of COPD, is a clinical diagnosis for a nonspecific disease that primarily affects adults. An in-depth presentation of the spectrum and management of COPD is given in Chapter 16. This section will focus solely on chronic bronchitis, a disease that affects most patients with COPD but can develop in patients with normal spirometry.22 In developed countries the prevalence of chronic bronchitis is slightly higher in men than in women and possibly more common in whites.22,23

Images Chronic bronchitis is defined clinically as the presence of a chronic cough productive of sputum lasting more than 3 consecutive months of the year for 2 consecutive years without an underlying etiology of bronchiectasis or tuberculosis. The disease is a result of several contributing factors; the most prominent include cigarette smoking, exposure to occupational dusts, fumes, and environmental pollution, and host factors (e.g., genetic factors and bacterial [and possibly viral] infections). The contribution of each of these factors and of others (either alone or in combination) to chronic bronchitis is unknown. Cigarette smoke is a well-known airway irritant and is believed to be the predominant factor in the etiology of chronic bronchitis. Although previously assumed the most common etiologic cause of chronic bronchitis, more strict prohibition of public smoking and the resultant decrease in chronic tobacco smokers, particularly in developed countries, underscores the importance of other factors as causes of this chronic disease. Additional airway irritants including occupational dust, chemicals, or air pollution, either alone or more probably in combination, are also responsible for the pathogenesis of chronic bronchitis. Furthermore, genome-wide association studies have begun to identify single-nucleotide polymorphisms that may have clinical relevance in COPD; see Chapter 16.24 Lastly, the influence of recurrent respiratory tract infections during childhood or young adult life on the later development of chronic bronchitis remains obscure, but recurrent respiratory infections may predispose individuals to the development of chronic bronchitis.23 Whether these recurrent respiratory tract infections are a result of unrecognized anatomic abnormalities of the airways or impaired pulmonary defense mechanisms is unclear.

Numerous consensus statements and published authoritative guidelines define chronic bronchitis and emphysema as the two main components of COPD/chronic obstructive lung disease (COLD).22,23,25 The Global Initiative for Chronic Obstruction Lung Disease (GOLD)22 guidelines document does not distinguish these two diagnoses (e.g., emphysema or chronic bronchitis) in the definition of COPD, but it does define COPD as a disease characterized by airflow obstruction that is not fully reversible and progressive. The GOLD guidelines provide a COPD classification scoring system according to severity that can be helpful in staging patients for intensity of therapy and prognosis.22Unfortunately, differences in definitions between authoritative organizations22,23,25 may cause confusion in the assignment of patients in clinical trials and thus to assessment and applications of study results to clinical care.

Pathogenesis

Chronic inhalation of an irritating noxious substance compromises the normal secretory and mucociliary function of bronchial mucosa.23 Bronchial biopsy specimens in bronchitic patients underscore the importance of proinflammatory cytokines (e.g., interleukins 1β, 6, and 8, transforming growth factor-β, leukotriene B4, and tumor necrosis factor-α) in the pathogenesis and propagation of the observed inflammatory changes. In chronic bronchitis, the bronchial wall is thickened, and the number of mucus-secreting goblet cells on the surface epithelium of both larger and smaller bronchi is increased markedly. In contrast, goblet cells generally are absent from the smaller bronchi of normal individuals. In addition to the increased number of goblet cells, hypertrophy of the mucous glands and dilation of the mucous gland ducts are observed. As a result of these changes, chronic bronchitics have substantially more mucus in their peripheral airways, further impairing normal lung defenses. This increased quantity of tenacious secretions within the bronchial tree frequently causes mucous plugging of the smaller airways. Accompanying these changes are squamous cell metaplasia of the surface epithelium, edema, and increased vascularity of the basement membrane of larger airways and variable chronic inflammatory cell infiltration. In addition, the amounts of several proteases derived from inflammatory cells are increased and due to COPD-induced defective antiproteases lead to continued destruction of connective tissue. Continued progression of this pathology can result in residual scarring of small bronchi and peribronchial fibrosis augmenting airway obstruction and weakening of bronchial walls.

Clinical Presentation

Images The hallmark of chronic bronchitis is a cough that may range from a mild to a severe, incessant coughing productive of purulent sputum.22,23 Coughing may be precipitated by multiple stimuli, including simple, normal conversation. Expectoration of the largest quantity of sputum usually occurs on arising in the morning, although many patients expectorate sputum throughout the day. The expectorated sputum usually is tenacious and can vary in color from white to yellow-green. Patients with chronic bronchitis often expectorate as much as 100 mL/day more than normal. As a result, many patients complain of a frequent bad taste in their mouth and of halitosis.

The diagnosis of chronic bronchitis is based primarily on clinical assessment and history. Any patient who reports coughing sputum on most days for at least 3 consecutive months each year for 2 consecutive years presumptively has chronic bronchitis.23 The diagnosis of chronic bronchitis is made only when the possibilities of bronchiectasis, cardiac failure, cystic fibrosis, and lung carcinoma have been effectively excluded. In an attempt to be more specific in the diagnosis, some investigators have added the criteria of lost wages for 3 or more weeks. In addition, many clinicians attempt to subdivide their patients based on severity of disease to guide therapeutic interventions. A useful diagnostic/clinical severity-based classification system is often used to categorize patients to assist in defining an acute therapeutic strategy. The classification system used most often utilizes three descriptive categories: (a) simple chronic bronchitis best describes patients with no major risk factors and sputum flora reflects the common associated pathogens where the patient usually responds well to first-line oral antibiotic therapy. (b) Complicated chronic bronchitis refers to those patients with what would be considered a “simple chronic bronchitis” exacerbation, but the patients have two or more disease-associated risk factors such as forced expiratory volume in the first second of expiration (FEV1) <50% (<0.50) predicted, age >64 years, >4 exacerbations per year, home oxygen use, underlying cardiac disease, use of immunosuppressants, or use of antibiotics for an exacerbation within the past 3 months. These group II patients may also harbor drug-resistant pathogens. (c) Severe complicated chronic bronchitis refers to those patients with group II symptoms but clinically are much worse, for example, FEV1 <35% (<0.35) predicted, >4 acute exacerbations per year, increased risk for infection with P. aeruginosa, and presence of pathogens that are multidrug resistant (MDR). The latter patients often require hospitalization and aggressive parenteral antibiotics including combination therapy. A clinical algorithm for the diagnosis and treatment of chronic bronchitic patients with an acute exacerbation incorporating the principles of the clinical classification system is shown in Figure 85–1. The importance of accurate classification for grouping patients of similar disease involvement cannot be overemphasized with respect to assessing publications outlining treatment strategies for these patients.26 Although gross, these classifications attempt to capture specific phenotypes of chronic bronchitis patients. It is hoped that within the next 2 to 4 years, pharmacogenomic advances will provide a more sophisticated tool for defining specific phenotypes linked to specific, optimal therapies.27 The typical clinical presentation of chronic bronchitis is listed in Table 85–1. Comparison of the trends in changes in patient’s physical activity, symptoms, and clinical/physical findings from the patient’s “routine” is extremely helpful in determining the presence and severity of an acute exacerbation. In general, a good clinical relationship exists between the purulence of the sputum and the bacterial load (>90% of cases) and for sputum color, for example, the greener the color, the greater the amount of leukocyte myeloperoxidase (indicating that more inflammatory cells are present).

Images

FIGURE 85-1 Clinical algorithm for the diagnosis and treatment of chronic bronchitic patients with an acute exacerbation incorporating the principles of the clinical classification system. (AECB, acute exacerbation of chronic bronchitis; COPD, chronic obstructive pulmonary disease; CB, chronic bronchitis; TMP/SMX, trimethoprim/sulfamethoxazole.) aSee Table 85–3 for commonly used antibiotics and doses. (Adapted from reference 34.)

TABLE 85-1 Clinical Presentation of Chronic Bronchitis

Images

In more advanced stages of chronic bronchitis, physical findings associated with cor pulmonale, including cardiac enlargement, hepatomegaly, and edema of the lower extremities, are observed. In general, chronic bronchitics tend to maintain at least normal body weight and commonly are obese. Radiographic studies are of limited value in either the diagnosis or followup of a patient. The microscopic and laboratory assessments of sputum are considered important components in the overall evaluation of patients with chronic bronchitis. A fresh sputum specimen obtained as an early morning sample is preferred. Comparison of the cellular constituents of chronic bronchitic sputum with those of normal sputum can provide insight into the degree of activity of the disease processes. An increased number of polymorphonuclear granulocytes often suggests continual bronchial irritation, whereas an increased number of eosinophils suggests an allergic component that should be further investigated. Gram staining of the sputum often reveals a mixture of both gram-positive and gram-negative bacteria, reflecting normal oropharyngeal flora and chronic tracheal colonization (in order of frequency) by nontypeable H. influenzaeS. pneumoniae, and M. catarrhalisTable 85–2 lists the most common bacterial isolates identified from sputum culture for patients experiencing an acute exacerbation of chronic bronchitis (AECB). For patients with more severe airflow disease (e.g., FEV1 <40% [<0.40]), enteric gram-negative bacilli, E. coliKlebsiella species, Enterobacter species, and P. aeruginosa may be significant pathogens during acute exacerbations.28

TABLE 85-2 Common Bacterial Pathogens Isolated from Sputum of Patients with Acute Exacerbation of Chronic Bronchitis

Images

TREATMENT

Desired Outcome

The goals of therapy for chronic bronchitis are twofold: to reduce the severity of chronic symptoms and to ameliorate acute exacerbations and achieve prolonged infection-free intervals.

General Approach to Treatment

The approach to treatment of chronic bronchitis is multifactorial.23 First and foremost, attempts must be made to reduce the patient’s exposure to known bronchial irritants (e.g., smoking, workplace pollution). A complete occupational and environmental history for determination of exposure to noxious, irritating gases, as well as preference toward cigarette smoking, must be assessed. Often easier discussed than accomplished, honest, yet reasonable attempts should be made with the patient to reduce or eliminate the number of cigarettes smoked daily and to reduce exposure to secondhand smoke. In an organized, coordinated, smoking cessation program, including counseling and hypnotherapy, the adjunctive use of nicotine substitutes (e.g., nicotine gum or patch) or other pharmacotherapy (e.g., bupropion, varenicline) may promote the reduction or complete withdrawal from cigarette smoking. Often just as difficult is modification of exposure to irritating substances within the home and workplace.

Images Measures to provide pulmonary toilet can be instituted. During acute pulmonary exacerbations of the disease, the patient’s ability to mobilize and expectorate sputum may be reduced dramatically. In these instances, attempts at postural drainage techniques, with instruction, active participation, or both from a respiratory therapist, may assist in promoting clearance of pulmonary secretions. In addition, humidification of inspired air may promote the hydration (liquefaction) of tenacious secretions, allowing for removal that is more productive. Use of mucolytic aerosols, such as N-acetylcysteine and DNAse, is of questionable therapeutic value, particularly considering their propensity to induce bronchospasm (N-acetylcysteine) and their excessive cost. A Cochrane meta-analysis of mucolytic therapy in subjects with chronic bronchitis or COPD found that treatment with mucolytics was associated with a small reduction in acute exacerbations and did not cause any harm, improve quality of life, or slow the decline of lung function.29 The clinical benefit may be greater for chronic bronchitics/COPD patients who have frequent or prolonged exacerbations and are unable to utilize inhaled corticosteroids or long-acting β2-agonists.29 Although limited data are available, chronic use of oral or aerosolized bronchodilators may be of benefit by increasing mucociliary and cough clearance. For patients with moderate to severe COPD, combination therapy with a long-acting β2-agonist and inhaled corticosteroid led to decreased exacerbations and rescue medication use while it also improved quality of life, lung function, and symptom scores compared with long-acting β2-agonist monotherapy.30 Furthermore, patients may benefit from inhaled corticosteroids; patients with severe disease (FEV1 <50% [<0.50]) with a history of frequent exacerbations should receive chronic inhaled corticosteroid therapy. Phosphodiesterase 4 (PDE4) inhibitors are a new class of drug approved for use in chronic bronchitis as add-on therapy for Group C and D COPD patients22,31,32 (see Chap. 16 for a full description of COPD classifications); use of systemic corticosteroid therapy (oral or IV) for patients with an acute exacerbation significantly reduces treatment failures and the need for additional medical treatment.22 Finally, in the face of an acute exacerbation, a trial of antibiotics directed against the most likely underlying pathogens should be initiated.

Pharmacologic Therapy

For patients who consistently demonstrate clinical limitation in airflow, a therapeutic challenge of a short-acting β2-agonist bronchodilator (e.g., as albuterol aerosol) should be considered. Pulmonary function tests should be performed before and after β2-agonist aerosol administration for more objective determination of a patient’s propensity to benefit from supplemental aerosol therapy. Sufficient published experience supports the use of inhalation therapy with a β2-agonist for patients with chronic bronchitis (COPD) to improve pulmonary function and exercise tolerance and to reduce the sense of breathlessness.23 Regular use of a long-acting β-receptor agonist aerosol (e.g., salmeterol, formoterol) in responsive patients may be more effective and probably more convenient than short-acting β2-receptor agonists. The aerosol route for β2-receptor agonist and/or corticosteroid administration is favored over systemic formulations for improved patient acceptance and compliance and to minimize the number and magnitude of associated adverse effects.22 Chronic inhalation of the salmeterol/fluticasone combination has been associated with improved pulmonary function and quality of life.

Published experience with inhaled anticholinergic drugs, including ipratropium and tiotropium, is limited. In stable patients, long-term inhalation of ipratropium has been associated with a decreased frequency of cough, less severe coughing, and a decrease in the volume of expectorated sputum. Once-daily tiotropium inhalation was associated with significant bronchodilation and dyspnea relief compared with placebo but had no significant effect on the incidence or severity of cough.22,23 Although chronic theophylline administration has been used extensively in the past, this therapy is used with decreasing frequency in favor of aerosolized β2-receptor agonists. A salmeterol/fluticasone combination markedly reduced the number of chronic bronchitis–associated emergency room visits and hospitalizations compared with an ipratropium-based regimen.33

PDE4 inhibitors, compared with the nonselective phosphodiesterase inhibitor theophylline, only affect phosphodiesterase in the airway smooth muscle, immune (eosinophils, monocytes, and neutrophils), and proinflammatory cells. Roflumilast, the only available PDE4 inhibitor, was approved by the U.S. FDA in 2011 for use in patients with severe COPD with chronic bronchitis and a history of exacerbations. Moderate to severe exacerbations treated with steroids were reduced by 15% to 20% in patients receiving roflumilast and add-on therapy with long-acting β2-agonists had effects on lung function.22 GOLD guidelines suggest the use of PDE4 inhibitors as an alternative therapy for COPD Group C patients with chronic bronchitis and as add-on therapy for COPD Group D patients with chronic bronchitis.22 The side effect profile for PDE4 inhibitor differs from inhaled COPD medications; patients may experience nausea, vomiting, decreased appetite, and sleep disturbances.22,32 Intolerable nausea and vomiting had occurred with cilomilast, a PDE4 inhibitor primarily targeting isozyme PDE4D located in the CNS compared with isozyme PDE4B, which is located in immune and proinflammatory cells.31 Roflumilast is nonselective for the PDE4 isozymes and is less likely to cause nausea and vomiting. Unexplained weight loss has also been reported in studies; therefore, a patient’s weight should be taken into consideration prior to treatment and monitored during therapy.

Use of antimicrobials for treatment of chronic bronchitis has been controversial but is becoming more accepted. Numerous comparative evaluations, including placebo-controlled studies of antibiotic administration with acute and chronic treatment of chronic bronchitics, have suggested definite clinical benefit, whereas other similar studies have not.22,25,26,28,34 The antibiotics selected most frequently possess variable in vitro activity against the common sputum isolates H. influenzaeS. pneumoniaeM. catarrhalis, and M. pneumoniae. Conflicting published results appear independent of the antibiotic used or the regimen compared. The wide disparity that exists in the results from these studies, combined with the difficulties in recognition and lack of standardized diagnostic criteria for acute exacerbations of chronic bronchitis, serves as the basis for the enormous controversy surrounding the use of antibiotics in this condition.23 A review of 14 double-blinded, randomized clinical trials compared fluoroquinolones with more standard antibiotic regimens (e.g., macrolides, azalides, oral cephalosporins, and the combination drug amoxicillin/clavulanate).28 As expected, no significant differences were observed between treatment arms. However, in a small subset of studies (n = 4), the sputum culture became negative in a significantly higher number of fluoroquinolone-treated patients. Other studies showed an increase in the interval between acute exacerbations for patients who received fluoroquinolone therapy. An additional advantage of fluoroquinolone therapy is the short course (e.g., 5 days) and once-daily dosing compared with other antibiotic regimens.

A useful paradigm for the assessment and treatment of acute exacerbations of chronic bronchitis and antibiotic decision making is shown in Figure 85–1. Furthermore, many clinicians will use the so-called Anthonisen criteria to determine if antibiotic therapy is indicated.35 With the Anthonisen criteria if a patient exhibits two of the following three criteria during an AECB, the patient will most likely benefit from antibiotic therapy and, thus, should receive a treatment course: (a) increase in shortness of breath; (b) increase in sputum volume; (c) production of purulent sputum. There are greater healthcare costs for patients who are noncompliant with their antibiotic regimen for their AECB.36

The increasing resistance of the common bacterial pathogens to first-line agents further complicates antibiotic selection. As many as 30% to 40% of H. influenzae and 95% to 100% of M. catarrhalis isolates produce β-lactamases. Moreover, up to 40% of S. pneumoniae isolates demonstrate resistance to penicillin (minimum inhibitory concentration [MIC] = 0.1 to 2 mg/L), with approximately 20% of isolates being highly resistant (MIC >2 mg/L). Concern regarding S. pneumoniae resistance is increasing, now ≥30% for macrolides. Despite these changes in bacterial susceptibility, the current recommendation is to initiate therapy with first-line agents in less severely affected patients (see Fig. 85–1). Trimethoprim/sulfamethoxazole has been extremely useful for patients with less severe disease.37 However, the public campaign in the United Kingdom by the Committee of Safety of Medicines to discourage the use of trimethoprim/sulfamethoxazole based on rare but possibly life-threatening cases of Stevens-Johnson syndrome has markedly reduced the use of this agent worldwide. For patients with more moderate to severe disease, many clinicians will begin antibiotic therapy with the second-line agents, amoxicillin/clavulanate, a macrolide (such as azithromycin or clarithromycin, although they are being used less frequently), and more frequently with a fluoroquinolone, such as levofloxacin (see Fig. 85–1).22,28,34,38

Regardless of the antibiotic selected, predetermined outcome measures should be monitored closely for each patient to determine the success or failure of the therapeutic intervention. Oral antibiotics with broader antibacterial spectra (e.g., amoxicillin/clavulanate, fluoroquinolones, or azalides) that possess potent in vitro activity against sputum isolates are increasingly becoming first-line antibiotics as initial therapy for treatment of acute exacerbations of chronic bronchitis.22,28,33,34,37

An important clinical outcome variable directing drug selection and criteria for beginning antibiotics in individual patients is the infection-free period when chronic bronchitics are off antibiotics. The actual length of the infection-free time period and the change in the number of physician office visits and hospital admissions with a particular antibiotic regimen are extremely important to identify, whenever possible, for each patient. The antibiotic regimen that results in the longest infection-free period defines the “regimen of choice” for specific patients for future acute exacerbations of their disease. Trials of prophylactic antibiotic use may provide a slight benefit in exacerbation rates; however, GOLD guidelines do not currently support this indication.22

Antibiotics should be selected that are effective against responsible pathogens, demonstrate the least risk of drug interactions, and can be administered in a manner that promotes compliance. Antibiotics commonly used for treatment of these patients and their respective adult starting doses are listed in Table 85–3. Doses of antibiotics should be adjusted as needed to the desired clinical effect and the lowest incidence of acceptable side effects. A frequently used clinical strategy to enhance the duration of symptom-free periods incorporates higher-dose antibiotic regimens using the upper limit of the recommended daily antibiotic dose for a period of 5 to 7 days. More clinicians are electing to limit their antibiotic treatment regimen to 5 days as compelling data continue to support equal efficacy and possibly less side effects with short-duration antibiotic therapy versus longer treatment regimens (>7 days).39

TABLE 85-3 Oral Antibiotics Commonly Used for the Treatment of Acute Respiratory Exacerbations in Chronic Bronchitis

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BRONCHIOLITIS

Epidemiology and Etiology

Images Bronchiolitis is an acute viral infection of the lower respiratory tract that affects approximately 50% of children during the first year of life and 100% by age 2 years. The occurrence of bronchiolitis peaks during the winter months and persists through early spring. Bronchiolitis remains the major reason for hospital admission during the first year of life. The incidence of bronchiolitis appears to be more common in males than in females.40,41

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis, accounting for up to 75% of all cases. During epidemic periods, the incidence of RSV-induced bronchiolitis may approach 90% of cases. Other detectable viruses include parainfluenza, adenovirus, and influenza. Bacteria serve as secondary pathogens in a minority of cases.40,42

Clinical Presentation

A prodrome suggesting an upper respiratory tract infection, usually lasting from 2 to 8 days, precedes the onset of clinical symptoms (Table 85–4). Due to limited oral intake because of coughing combined with fever, vomiting, and diarrhea, infants frequently are dehydrated. The increased work of breathing and tachypnea most likely further increase fluid loss. In most cases, this clinical picture persists between 3 and 7 days. Although the hospital course of bronchiolitic children often is variable, substantial clinical improvement usually is observed within the first 2 days, with gradual improvement and complete resolution sometimes requiring 4 to 8 weeks.

TABLE 85-4 Clinical Presentation of Bronchiolitis

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The diagnosis of bronchiolitis is based primarily on history and clinical findings. It is important for the clinician to attempt to differentiate between bronchiolitis and a host of other clinical entities affecting infants, which may produce a similar picture of dyspnea and wheezing. Asthma, congestive heart failure, anatomic airway abnormalities, cystic fibrosis, foreign bodies, and gastroesophageal reflux are the primary disease entities that may present with wheezing in children. Isolation of a viral pathogen in the respiratory secretions of a wheezing child establishes a presumptive diagnosis of infectious bronchiolitis. However, the ability to identify specific viral pathogens often is hindered by the limited availability of special virology laboratories. In addition, in the elderly and in immunocompromised patients, antigen detection lacks adequate sensitivity, and patients frequently seek medical care after the acute stage of the infection, thus compromising the ability of the available tests to diagnose RSV. However, the proliferation of commercial enzyme-linked immunosorbent assays and fluorescent antibody staining techniques of nasopharyngeal secretions has increased the ability to identify viral antigens within several hours.40 Identification of RSV by PCR should be available routinely from most clinical laboratories, but its relevance to the clinical management of bronchiolitis remains obscure.

Multiple clinical laboratory determinations have been used to assist in the management of cases of bronchiolitis. Radiographic evaluation of the chest in children with bronchiolitis yields variable findings but may help to distinguish this illness from other entities characterized by wheezing. In children requiring hospitalization, abnormalities in blood gas tensions are frequent and appear to relate to disease severity. Hypoxemia is common and increases the respiratory drive, whereas hypercarbia is seen in only the most severe cases. Despite the presence of moderate degrees of hypoxemia, clinical cyanosis is unusual.

TREATMENT

Desired Outcome

Images In the well infant, bronchiolitis usually is a self-limiting illness, and reassurance, antipyretics, and adequate fluid intake usually are all that are necessary while waiting for resolution of the underlying viral infection. In-hospital support is necessary for the child suffering from respiratory failure or marked dehydration; underlying cardiac and pulmonary diseases potentiate these conditions.

General Approach to Treatment

Images Almost all otherwise healthy babies with bronchiolitis can be followed as outpatients. Such infants are treated for fever, provided generous amounts of oral fluids, and observed closely for evidence of respiratory deterioration.43In severely affected children, the mainstays of therapy for bronchiolitis are oxygen therapy and IV fluids. In a subset of patients, aerosolized bronchodilators may have a role. For selected infants, particularly those with underlying pulmonary disease, cardiac disease, or both, therapy with the antiviral agent ribavirin can be considered.44

Pharmacologic Therapy

Images Aerosolized β2-adrenergic therapy appears to offer little benefit for the majority of patients and may even be detrimental.40,42 However, this therapy may offer some benefit to the child with a predisposition toward bronchospasm. In addition, although clinical trials have demonstrated varied results, nebulized epinephrine seems to be more efficacious than albuterol in hospitalized patients with bronchiolitis.40,45 For such patients, bronchodilator therapy may be offered initially but should not be pursued in the absence of a clear-cut clinical benefit. Similarly, controlled trials of corticosteroids in bronchiolitic infants have not shown therapeutic effects or significant harmful effects.42,44 As a result, the routine use of systemically administered corticosteroids is discouraged. Conversely, the combined use of oral dexamethasone with nebulized epinephrine may act synergistically to reduce hospital admissions and shorten the time to discharge and the duration of symptoms; however, more trials are needed to confirm these findings.45,46 Although placing children with bronchiolitis in mist tents has been common practice, no data have documented the effectiveness of this practice.

Ribavirin may offer benefit to a subset of infants with bronchiolitis. Although ribavirin, a synthetic nucleoside, possesses in vitro antiviral properties against a variety of RNA and DNA viruses, including influenza A, influenza B, parainfluenza, and adenovirus,41 it is approved only in aerosolized form against RSV. Use of the drug requires special equipment (small-particle aerosol generator) and specially trained personnel for administration via oxygen hood or mist tent. Special care must be taken to avoid drug particle deposition and the resulting clogging of respiratory tubing and valves in mechanical ventilators. Among hospital admissions for RSV infection, ribavirin therapy failed to decrease length of hospital stay, number of days in the intensive care unit, or number of days receiving mechanical ventilation. Consequently, the American Academy of Pediatrics does not recommend the routine use of ribavirin in children with bronchiolitis.47 In light of this and because of the requirement for special aerosolization equipment and the cost of the drug itself, most experts recommend reserving use of ribavirin for severely ill patients, especially those with chronic lung disease (particularly bronchopulmonary dysplasia), congenital heart disease, prematurity, and immunodeficiency (especially severe combined immunodeficiency and human immunodeficiency virus [HIV] infection).


Clinical Controversy…

Because bacteria are not primary pathogens in the etiology of bronchiolitis, antibiotics should not be administered routinely. Despite this, many clinicians frequently administer antibiotics while awaiting culture results because the clinical and radiographic findings in bronchiolitis often are suggestive of possible bacterial pneumonia.

For infants with underlying pulmonary or cardiovascular disease, prophylaxis against RSV may be warranted. When administered monthly during the RSV season, both RSV immune globulin and palivizumab48 (a monoclonal antibody for RSV) may decrease the number of RSV episodes and the need for hospitalization. Between the two, palivizumab appears to be preferred, given its ease of administration, lack of administration-related adverse effects, and noninterference with select immunizations.

There is no vaccine marketed for RSV. Of note, in the 1960s, a formalin-inactivated vaccine induced a promising IgG response; however, the severity of subsequent infections was increased in immunized patients. In addition, aside from the need to induce immunity to multiple strains of the virus, a series of boosters would be required as natural infection with RSV does not prevent subsequent infections.44

PNEUMONIA

Epidemiology

Pneumonia remains the most common cause of severe sepsis and infectious cause of death in children and adults in the United States, with a mortality rate of 30% to 40%.6,49 Pneumonia occurs throughout the year, with the relative prevalence of disease resulting from different etiologic agents varying with the seasons. It occurs in persons of all ages, although the clinical manifestations are most severe in the very young, the elderly, and the chronically ill.

Pathogenesis

Microorganisms gain access to the lower respiratory tract by three routes. They may be inhaled as aerosolized particles, or they may enter the lung via the bloodstream from an extrapulmonary site of infection; however, aspiration of oropharyngeal contents, a common occurrence in both healthy and ill persons during sleep, is the major mechanism by which pulmonary pathogens gain access to the normally sterile lower airways and alveoli. When pulmonary defense mechanisms are functioning optimally, aspirated microorganisms are cleared from the region before infection can become established; however, aspiration of potential pathogens from the oropharynx can result in pneumonia if lung defenses are impaired.7 Factors that promote aspiration, such as altered sensorium and neuromuscular disease, may result in an increase in the size of the inoculum delivered to the lower respiratory tract, thereby overwhelming local defense mechanisms. Lung infections with viruses suppress the antibacterial activity of the lung by impairing alveolar macrophage function and mucociliary clearance, thus setting the stage for secondary bacterial pneumonia. Mucociliary transport is also depressed by ethanol and narcotics and by obstruction of a bronchus by mucus, tumor, or extrinsic compression. All these factors can severely impair pulmonary clearance of aspirated bacteria.

Images The most prominent pathogen causing community-acquired pneumonia (CAP) in otherwise healthy adults is S. pneumoniae and accounts for up to 75% of all acute cases. Other common pathogens include M. pneumoniaeLegionella speciesC. pneumoniaeH. influenzae, and a variety of viruses including influenza.5,50 Healthcare-associated pneumonia (HCAP) is a classification used to distinguish nonhospitalized patients at risk for MDR pathogens (e.g., P. aeruginosaAcinetobacter species, and methicillin-resistant Staphylococcus aureus [MRSA]) from those with CAP.5,51 The term atypical may be applied to pneumonia to indicate that the pneumonia may be caused by an atypical pathogen (e.g., bilateral lobar pneumonia with a negative sputum Gram stain) such as M. pneumoniaeC. pneumoniae, or Legionella species.52

Gram-negative aerobic bacilli, S. aureus, and MDR pathogens are the leading causative agents in hospital-acquired pneumonia (HAP).7 Anaerobic bacteria are the most common etiologic agents in pneumonia that follows the aspiration of gastric or oropharyngeal contents. Ventilator-associated pneumonia (VAP) is also associated with MDR pathogens.

Pneumonia in infants and children is caused by a wider range of microorganisms, and, unlike adults, nonbacterial pathogens predominate. Most pneumonias occurring in the pediatric age group are caused by viruses, especially RSV, parainfluenza, and adenovirus.6 M. pneumoniae is an important pathogen in older children. Beyond the neonatal period, S. pneumoniae is the major bacterial pathogen in childhood pneumonia, followed by group A Streptococcus and S. aureus. H. influenzae type b, once a major childhood pathogen, has become an infrequent cause of pneumonia since the introduction of active vaccination against this organism in the late 1980s.

Based on the differences in severity and outcome for patients with CAP, genetic factors likely play a role.53 Multiple variations in genes affecting inflammation, cough and airway protection, pattern recognition molecules, and organ function along with environmental factors may alter a patient’s response to CAP. In the future, as specific genetic polymorphisms are better associated with disease response, therapy should become better targeted.

Clinical Presentation

Bacterial pneumonia is caused most commonly by gram-positive streptococci and staphylococci and by gram-negative organisms that normally inhabit the GI tract (enterics) or soil and water (nonenterics). In addition, Legionella, itself a weakly staining gram-negative nonenteric organism, accounts for a small percentage of CAP and HAP, although the true incidence may be underreported.52 Finally, M. tuberculosis, an acid-fast staining bacillus, still remains an important cause of pneumonia in urban centers throughout the United States even though the incidence is much lower compared with that in other countries.54,55

A wide array of gram-positive and gram-negative organisms can cause pneumonia, but they usually present a similar clinical appearance (Table 85–5); thus, the epidemiologic and clinical clues will render one more likely than the other. S. pneumoniaeS. aureus, the enteric gram-negative rods, and occasionally other organisms may produce local irritation or destruction of blood vessels leading to rust-colored sputum or hemoptysis. Pleural effusions, both sterile and empyematous, may be associated with many of these entities, as evidenced by distant breath sounds and a wide area of dulled percussion. The chest radiograph and sputum examination and culture are the most useful diagnostic tests for gram-positive and gram-negative bacterial pneumonia.5 Typically, the chest radiograph reveals a dense lobar or segmental infiltrate. However, patchy consolidation may be seen occasionally with virtually all these pathogens. Occasionally, pneumonia resulting from hematogenous spread of the organisms results in a diffuse, alveolar pattern on chest radiograph. Gram stain of the expectorated sputum demonstrates many polymorphonuclear cells per high-powered field in the presence of a predominant organism, which is reflected as heavy growth of a single species on culture. Other laboratory tests are less sensitive or specific. Blood cultures may be helpful in identifying the offending organism but are positive in only a minority of patients. The complete blood count usually reflects a leukocytosis with a predominance of polymorphonuclear cells; in some instances, particularly with S. pneumoniae, elevation of the white blood cell (WBC) count may be pronounced. Normal or mildly elevated WBC counts, however, do not exclude bacterial pneumonic disease. The patient also may be hypoxic, as reflected by low oxygen saturation on arterial blood gas or pulse oximetry.

TABLE 85-5 Clinical Presentation of Pneumonia

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Community-Acquired Pneumonia

Images S. pneumoniae is the most common community-acquired bacterial pneumonia in adult and pediatric patients.5,6 It is particularly prevalent and severe for patients with splenic dysfunction, diabetes mellitus, chronic cardiopulmonary or renal disease, or HIV infection. Community-acquired disease with S. aureus is identified most frequently in young infants, patients with early cystic fibrosis, and those recovering from an antecedent respiratory viral infection. Group A Streptococcus is an uncommon cause of CAP and frequently occurs after a viral respiratory tract infection. Only occasionally is it associated with streptococcal pharyngitis. The organism is pyogenic, and the presentation can be severe. Community-acquired enteric gram-negative pneumonia is identified most frequently among patients with chronic illness, especially alcoholism and diabetes mellitus. In preschool-aged children, viral pathogens more commonly cause CAP compared with bacterial pathogens.6

Severity scores (e.g., CURB-65 and PSI), with varying strengths and weaknesses, have been utilized to assist healthcare professionals in predicting intensive care hospitalization and outcomes for patients with CAP.5,56,57Definitions of severe CAP may vary depending on the institution; however, patients with severe CAP are more likely to require intensive care or mechanical ventilation, or develop complications with sepsis, bacteremia, or multiorgan failure.51 Severe CAP may also be difficult to distinguish from HCAP or HAP; however, the pathogens, S. pneumoniaeH. influenzae, and anaerobic bacteria, are not usually MDR. Patients at greater risk for severe CAP are those with underlying medical conditions or at risk for aspiration, animal exposure, or exposure to other infected patients or seasonal epidemics.51

Healthcare-Associated Pneumonia

Over the past several decades, the type of facilities where patients can receive healthcare has changed with infusion therapies, wound care, and dialysis available in an outpatient environment.58 This, along with patients residing in a nursing home or long-term care facility or patients recently discharged from a hospital, has blurred the distinction between the pneumonia acquired as an inpatient versus an outpatient. See Table 85–6 for HCAP criteria. Patients diagnosed with HCAP are more similar to hospitalized patients based on comorbid conditions (e.g., heart disease, chronic kidney disease, immunocompromised, or dementia) than patients with CAP and are at a greater risk for MDR pathogens.7,51 The more common pathogens isolated from residents of long-term care facilities/nursing homes have MRSA, enteric gram-negative rods, and Pseudomonas species.7 Compared with patients with CAP, patients with HCAP are more likely to receive inappropriate antibiotics initially and have a higher risk of mortality.59 Thus, it is important to recognize the difference between HCAP and CAP for appropriate empirical antibiotics.

TABLE 85-6 Pneumonia Classifications and Risk Factors

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Pneumonia in the HIV-Infected Patient

A broad range of pathogens can cause pneumonia in HIV infection (Table 85–7) including opportunistic infections such as P. jiroveci and Mycobacterium species.60 These patients may be afflicted with pneumonia multiple times in their lifetime, particularly in the advanced stages of the disease, and a given episode may be caused by more than one species. The clinical presentation of pneumonia in HIV-infected persons frequently is not helpful in distinguishing one pathogen from another. The pneumonia usually is subacute in onset and consists of fever, nonproductive cough, and dyspnea. Radiographically, most of these entities produce a multilobular or diffuse pattern. Some practitioners initially treat the HIV-infected patient with pneumonia empirically; however, given the wide array of possible pathogens, more frequently a specific microbiologic diagnosis is aggressively pursued early in the patient’s course through sputum induction or bronchoalveolar lavage to allow a rational choice of an antimicrobial regimen. The diagnosis and treatment of HIV-infected patients with pulmonary disease is discussed in detail in Chapter 103.

TABLE 85-7 Pulmonary Complications of Human Immunodeficiency Virus Infection

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Pneumonia in the Neutropenic Host

Neutropenia in the cancer patient is a common complication of aggressive chemotherapy but occasionally results from the cancer itself. The risk of infection for the cytopenic patient is increased significantly when the absolute neutrophil count falls below 500 cells mm3 (500 × 106/L) and the neutropenia persists for more than 7 days. For many patients, the duration of chemotherapy-induced cytopenia can be reduced by judicious application of colony-stimulating factors.61

The organisms that cause pneumonia in the cytopenic cancer patient include a broad range of bacteria and fungi. The most prominent among these are gram-positive bacteria (staphylococci and streptococci); others include enteric and nonenteric (particularly P. aeruginosa) gram-negative rods as well as the fungi (CandidaAspergillus). The chest radiograph may reveal the lobar pattern typical of bacterial infection in the normal host, or it may exhibit a diffuse pattern. Sometimes the pneumonia remains invisible by chest radiograph until the neutropenia resolves. Noninfectious entities that may cause pulmonary symptoms include toxicity from radiation or chemotherapy or infiltration of the lung parenchyma by the tumor itself.

Hospital-Acquired Pneumonia

After the urinary tract and the bloodstream, the lungs are the most frequent site of infection acquired in the hospital. HAP is seen most commonly in critically ill patients and usually caused by bacteria.7Factors predisposing patients to the development of HAP include the severity of illness, duration of hospitalization, supine positioning, witnessed aspiration, coma, acute respiratory distress syndrome, patient transport, and prior antibiotic exposure (see Table 85–6). The strongest predisposing factor, however, is mechanical ventilation (intubation). The length of stay for hospital admissions is increased, on average, by 7 to 9 days for patients who develop HAP.7

The organisms most commonly associated with HAP are S. aureus and enteric (e.g., K. pneumoniae or E. coli) and nonenteric (e.g., P. aeruginosa) gram-negative bacilli, organisms that colonize the pharynx of the hospitalized, critically ill patient. Patients with longer lengths of hospital admission prior to the development of HAP are more likely to have MDR organisms.7 The diagnosis of HAP usually is established by the presence of a new infiltrate on chest radiograph, fever, worsening respiratory status, and the appearance of thick, neutrophil-laden respiratory secretions. In actuality, the diagnosis often is difficult to make in the intensively ill patient with underlying lung pathology that itself can be associated with an abnormal changing radiograph, as occurs with congestive heart failure or chronic lung disease. If a patient develops fever, leukocytosis, and purulent sputum, and has positive sputum/tracheal cultures but radiographic imaging does not indicate new infiltrates, he or she may have tracheobronchitis as opposed to HAP.7 Broad-spectrum antibiotics frequently are started empirically even in equivocal circumstances, with bronchoscopy reserved for poorly responsive patients.7

Gram-Positive Bacteria

S. aureus is a prominent cause of HAP and may result from hematogenous spread from a distant source. It is characteristically severe and accompanied by the formation of pneumatoceles (air-containing cavities within the lung). Infections caused by MDR organisms such as MRSA and vancomycin-intermediate and vancomycin-resistant S. aureus are increasing among patients with HAP. Group B Streptococcus, although rare in adults, is the most common cause of bacterial pneumonia among neonates, in whom it typically causes a clinical and radiographic picture nearly indistinguishable from hyaline membrane disease.62

Enteric Gram-Negative Bacteria

The enteric gram-negative bacteria are leading causes of HAP because the upper respiratory tract becomes rapidly colonized with gram-negative organisms after hospitalization, particularly among critically ill patients and those receiving antibiotics.63 K. pneumoniae is the most frequently encountered pathogen among the gram-negative enteric bacteria, although the relative prominence of these organisms varies among hospitals. The gram-negative bacilli are associated with high mortality, sometimes exceeding 50%; their potential to produce significant morbidity and mortality has been enhanced by the emergence of highly MDR organisms in some hospital settings.7

Nonenteric Gram-Negative Bacteria

The most prominent nonenteric gram-negative rods associated with pneumonia include P. aeruginosaH. influenzae, and M. catarrhalis. Like the enteric gram-negative organisms, P. aeruginosa is a frequent cause of HAP and is particularly prominent among neutropenic and burn patients.7 In addition, cystic fibrosis patients suffer from chronic, multilobar infections with P. aeruginosa, as well as other Pseudomonas species, and S. maltophilia is an emerging pathogen64; these infections are punctuated with acute exacerbations. H. influenzae type b historically has been a prominent pathogen in childhood pneumonia. The incidence of all invasive disease due to this organism in the pediatric age group has dropped dramatically since the introduction of the conjugated Haemophilus vaccines in the late 1980s. However, two different clinical presentations of H. influenzae pneumonia still are seen in adults. The most common by far is the bronchopneumonia form, which develops most frequently for patients with underlying chronic lung disease and is believed to represent, in most patients, an exacerbation of chronic bronchitis. In the second form of H. influenzae pneumonia, segmental or lobar involvement predominates. The course of this illness is more acute, with sudden onset of cough, fever, and pleuritic chest pain. Finally, M. catarrhalis, an important cause of otitis media and sinusitis, is an increasingly important cause of lower respiratory tract infections in immunocompromised and hospitalized patients.

Anaerobic Bacteria

Images Anaerobic pneumonitis is most likely to occur in individuals predisposed to aspiration by impaired consciousness or dysphagia as the source for the anaerobic bacteria is generally the oral cavity/gingival crevice.65 Bronchogenic carcinoma is an associated underlying condition. A variety of gram-positive and gram-negative anaerobic bacteria indigenous to the upper airway may cause pneumonitis when large quantities of oropharyngeal secretions are aspirated into the lower airways. The most common organisms identified are B. melaninogenicus, Fusobacteria, and anaerobic streptococci; polymicrobial infections with anaerobes and aerobes, such as S. aureusS. pneumoniae, and gram-negative bacilli, are common.65

Early in the infection, clinical symptoms are similar to CAP with patients presenting with cough, low-grade fever, pulmonary infiltrates, and leukocytosis. The course of anaerobic pneumonia is typically indolent and patients are unlikely to have rigors. Other characteristic features are lung abscess, necrotizing pneumonia, and empyema. Anaerobic infections should be suspected if patients are predisposed to aspiration or have a chronic course, putrid sputum/breath, pulmonary necrosis, or empyema.65 Chest radiographs reveal infiltrates typically located in dependent lung segments, and lung abscesses develop in 20% of patients 1 to 2 weeks into the course of the illness.

Ventilator-Associated Pneumonia

VAP is defined as pneumonia occurring >48 hours post–endotracheal intubation. The risk for developing pneumonia in the hospital increases by 6 to 21 times after a patient is intubated7 because it bypasses the natural airway defenses against the migration of upper respiratory tract organisms into the lower tract. This situation is exacerbated by the wide use of acid-reducing drugs (e.g., H2-receptor blocking agents, proton pump inhibitors) in the intensive care unit, which increases the pH of gastric secretions and may promote the proliferation of microorganisms in the upper GI tract. Subclinical microaspirations are events that occur routinely in intubated patients and result in the inoculation of bacteria-contaminated gastric contents into the lung and a higher incidence of nosocomial pneumonia.66 Pneumonia that develops within 4 days of hospitalization is more likely to be caused by an antibiotic sensitive organism such as S. pneumoniaeS. aureus, or Haemophilus species, whereas infections developing later are more likely to be MDR (e.g., P. aeruginosa, MRSA, Acinetobacter species). Outbreaks of VAP may be caused occasionally by contaminated respiratory therapy equipment.

To date, there is no “gold standard” for diagnosing VAP; thus, an accurate diagnosis is challenging. Most intensivists agree that VAP should be suspected if new or persistent infiltrates are found on chest radiograph along with ≥2 of the following: purulent tracheal secretions, leukocytosis or leucopenia, and body temperature >38.3°C (>100.94°F).9,66 Invasive (e.g., bronchoalveolar lavage) or noninvasive techniques may be used for obtaining samples of lower respiratory tract secretions for culture and sensitivity testing.66

Atypical Pneumonia

Legionella species, Mycoplasma species, Chlamydia species, viruses, and fungi are recognized causes of pneumonia syndromes in all age groups. The designation atypical pneumonia, distinct from the typical bacterial pneumonia course seen most commonly in adults, has been used to describe the illness caused by many of these agents.52,67

Legionella pneumophila

Of the several Legionella species known to cause pneumonia in humans, L. pneumophila is by far the most important, accounting for 4% to 9% of all CAPs in North America and Europe.52 Legionella, a small, gram-negative, non–spore-forming bacilli, is an aquatic organism that is transmitted by inhalation of aerosols containing the organism or by microaspiration of contaminated water. Outbreaks of illness caused by L. pneumophila have been linked to excavation sites and to contaminated water from air conditioners and showers. Person-to-person transmission has not been demonstrated. In addition to epidemics, L. pneumophila causes sporadic illness that peaks in summer and fall. Individuals who are male, middle aged or older, immunocompromised, chronic bronchitics, or cigarette smokers, or have used tumor necrosis factor-α antagonists are at increased risk.52

Infection with L. pneumophila is characterized by multisystem involvement and the severity of the infection can range from mild to severe, rapidly progressive pneumonia.57,67 It has a gradual onset, with prominent constitutional symptoms (e.g., malaise, lethargy, weakness, anorexia) occurring early in the course of the illness. A dry, nonproductive cough is present initially and becomes productive of mucoid or purulent sputum over several days. Fevers exceeding 40°C (104°F) develop in more than half of patients, typically are unremitting, and are associated with a relative bradycardia. Pleuritic chest pain and progressive dyspnea may be seen. Extrapulmonary symptoms, particularly diarrhea, nausea, and vomiting, remain evident throughout the course of the illness. Myalgias and arthralgias also occur. Substantial changes in the patient’s mental status, often out of proportion to the degree of fever, are seen in approximately one fourth of patients. Obtundation, hallucinations, grand mal seizures, and focal neurologic findings are also associated with this illness. Chest radiographs initially reveal patchy alveolar infiltrates that may be bilateral and asymmetric. Pulmonary infiltrates may worsen even when the patient is receiving appropriate antibiotics. Progression to lobar or multilobar consolidation is frequent, as are small pleural effusions.

Laboratory findings include leukocytosis with a predominance of mature and immature granulocytes in 50% to 75% of patients. Urinalysis may reveal proteinuria, hematuria, and casts; liver function tests may be abnormal and increases in serum creatine phosphokinase have occurred in patients with L. pneumophila.67 Hyponatremia and hypophosphatemia (typically occurring early in infection) have been reported frequently.67 Because L. pneumophilastains poorly with commonly used stains, routine microscopic examination of sputum is of little diagnostic value. Although it exhibits slow growth and has highly selective growth requirements, L. pneumophila has been isolated successfully from tissue using a specialized medium. Direct fluorescent antibody examination of respiratory tract secretions, lung tissue, or pleural fluid is the most rapid means of establishing the diagnosis. The sensitivity of this method approaches 70% for sputum and 90% for lung tissue, and diagnostic specificity is high for both. Commercially available urine antigen tests have been developed for L. pneumophila. These tests are 70% sensitive and remain positive for weeks, even after effective antibiotics have been started. Because these diagnostic tests are unavailable in many clinical laboratories, the diagnosis of Legionnaires’ disease often is presumptive and based on a suggestive clinical presentation.

M. pneumoniae

The mycoplasmas are included in their own taxonomy labeled Mollicutes. Although their small size and filterability are similar to viruses, the structure of their ribosomal RNA indicates that they have evolved from bacteria, and, unlike any virus, they contain cytoplasm and can replicate in an extracellular environment. They are distinguished from eubacteria by their low genetic content and have a parasitic relationship with their hosts.52 In addition, the mycoplasmas lack a cell wall and are surrounded instead by a lipid membrane. The latter characteristic explains the resistance of these pathogens to cell wall–active antibiotics.

M. pneumoniae causes human disease throughout the year, with a slightly increased incidence in fall and early winter. During the summer months when other causes of pneumonia are less common, M. pneumoniae is responsible for a greater proportion of cases. Both infection and disease from M. pneumoniae are common, with 10% to 30% of the cases of CAP in children and young adults attributed to this organism.68 In enclosed populations, such as military recruits and college dormitory residents, it may cause more than 50% of the cases of CAP. Infection is spread by close person-to-person contact, and the incubation period is 2 to 3 weeks. M. pneumoniae infections are unusual in children younger than 5 years and show a peak incidence in older children and young adults. Only 3% to 10% of persons infected with M. pneumoniae develop pneumonia, with the majority of respiratory tract involvement manifested as pharyngitis and tracheobronchitis. Asymptomatic infection is common.

M. pneumoniae usually presents with a gradual onset of fever, headache, and malaise, with the appearance 3 to 5 days after the onset of illness of a persistent, hacking cough that initially is nonproductive. Sore throat, ear pain, and rhinorrhea often are present. Chills are seen only occasionally, and pleuritic pain is uncommon. Lung findings generally are limited to rales and rhonchi; findings of consolidation are rare. Nonpulmonary manifestations of M. pneumoniae are extremely common and include nausea, vomiting, diarrhea, myalgias, arthralgias, polyarticular arthritis, and skin rashes while myocarditis, pericarditis, hemolytic anemia, meningoencephalitis, cranial neuropathies, and Guillain-Barré syndrome have also been reported.52,69 Systemic symptoms generally clear in 1 to 2 weeks, whereas respiratory symptoms may persist for up to 4 weeks. Although the course of mycoplasma pneumonia usually is benign and self-limited, severe respiratory disease may develop in patients with sickle cell disease, agammaglobulinemia, COPD, and splenectomy.52,67

Radiographic findings generally are more impressive than the patient’s physical findings and include patchy or interstitial infiltrates, which are seen most commonly in the lower lobes.67 Small unilateral, transient pleural effusions are common, but large effusions and empyema are rare. Radiographic abnormalities resolve slowly, and 4 to 6 weeks may be required for complete resolution.

Sputum Gram stain may reveal mononuclear or polymorphonuclear leukocytes, with no predominant organism. Although M. pneumoniae can be cultured from respiratory secretions using specialized medium, its growth is slow, and 2 to 3 weeks may be necessary for culture identification. Indirect evidence of infection by M. pneumoniae is the presence of elevated levels of serum cold hemagglutinins. These immunoglobulin M antibodies develop in approximately half of patients with mycoplasmal pneumonia and can be elevated in other illnesses, especially viral infection. A definitive diagnosis also can be made by demonstrating a fourfold or greater rise in serum antibodies to M. pneumoniae. However, because this test also requires 2 to 4 weeks for results, the diagnosis of mycoplasmal pneumonia during the acute phase of the illness must be based on the characteristic history, appropriate clinical setting, and typical physical findings.

C. pneumoniae

C. pneumoniae has received the new taxonomic classification of Chlamydophila; however, it may still be referred to as Chlamydia pneumoniae in some references.12 C. pneumoniae, formally designated the Taiwan acute respiratory (TWAR) agent after the laboratory designations for the first two isolates, is antigenically similar to C. psittaci. C. pneumoniae infection is ubiquitous worldwide; ~80% of the population has been infected by adulthood,52 but only a small percentage of infections result in clinically apparent pneumonia. Conversely, approximately 5% to 15% of pneumonia is associated with this pathogen.12 Primary infection with Chlamydia pneumonia typically occurs in young adults and is characterized by mild respiratory symptoms with a gradual onset (e.g., incubation period about 21 days). Constitutional manifestations, particularly fever, headache, and hoarseness, are common.52 The radiographic findings are nonspecific and usually consist of multilobular interstitial infiltrates with circumscribed lesions.67 Immunity is incomplete, and reinfection with C. pneumoniae is common, particularly among the elderly. Definitive diagnosis of C. pneumoniae–associated pneumonia depends on identification of the organism in sputum. Culture of this organism is difficult, and commercially available antigen detection systems are insensitive.

Viral Pneumonia

Viruses are an uncommon cause of pneumonia in adults, except in the immunosuppressed.7 Influenza virus, usually type A, is the most common viral cause of pneumonia in the adult civilian population5; other viruses causing adult CAP include RSV, adenoviruses, parainfluenza, and human metapneumovirus.5 In contrast, viruses are by far the most common agents producing pneumonia in infants and young children, up to 80% in <2-year-olds, with RSV accounting for most cases; other common viruses in children are parainfluenza, adenovirus, human metapneumovirus, bocavirus, and rhinovirus.6,40,52

All viral respiratory tract infections occur more commonly in the winter, and rapid person-to-person spread through susceptible populations is typical. Underlying cardiac or pulmonary disease predisposes to an increased incidence and severity of viral lower respiratory tract infection, especially with influenza virus in adults and RSV in children. Radiographic findings are nonspecific and include bronchial wall thickening and perihilar and diffuse interstitial infiltrates. Pleural effusions may be seen, especially in adenovirus and parainfluenza pneumonia.

The clinical pictures produced by respiratory viruses are sufficiently variable and overlap to such a degree that an etiologic diagnosis cannot be made confidently based on clinical grounds alone. Although virus isolation in tissue culture is still considered the gold standard, it is time consuming and technically demanding; a period of ≥7 days often is required for virus identification3; thus, this method usually cannot be used for definitive diagnosis during the acute phase of illness. Serologic tests for virus-specific antibodies are used often in epidemiologic and surveillance studies of viral infections since the diagnostic fourfold rise in titer between acute and convalescent phase sera may require 2 to 3 weeks to develop.3 Rapid antigen testing for the influenza virus (some tests distinguishing types A and B) and RSV is available; however, cost, high false-positive rates, and 50% to 70% sensitivity are considerations for its utility during nonpeak seasons.3,5,7 Viral testing with molecular techniques provides increased utility for patient care with high sensitivity, rapid results and the ability to detect new and emerging pathogens. Numerous testing methods are available, not all in the United States, including real-time PCR, solid and liquid microarrays, mass spectrometry, target-enriched multiplexing PCR, and multiplex ligation-dependent probe amplification, to name a few.3

Viruses that have emerged in recent decades and caused significant outbreaks include avian influenza H5N1, severe acute respiratory syndrome coronavirus (SARS-CoV), and swine influenza H1N1.7072 The first known cases of humans infected with avian H5N1 subtype occurred in Hong Kong in 1997, with 6 deaths among 18 infected patients. Signs and symptoms typical of the H5N1 virus are those common to other subtypes; however, pneumonia, respiratory distress syndrome, lymphopenia, and clotting abnormalities tend to occur rapidly in patients infected with this highly virulent subtype. In April 2009, a novel influenza A virus of swine origin, H1N1, was identified as the causative pathogen in an outbreak of respiratory illness and influenza-like illness in Mexico.72 Signs and symptoms of the H1N1 virus are similar to other subtypes; however, more serious infections have resulted in hospitalization and death. It has also affected normally healthy young adults as opposed to other flu viruses, which tend to be more severe in the young and the elderly.

SARS-CoV manifested in China in November 2002 and was an extremely contagious atypical pneumonia.73,74 The virus is transmitted primarily via large-droplet spread; however, surface contamination and airborne and fecal spread are possible. Signs and symptoms associated with SARS include high fever, myalgias, headache, diarrhea, and a dry nonproductive cough. Respiratory symptoms may progress to shortness of breath and hypoxemia, necessitating the need for intubation and mechanical ventilation. Diagnostic tests for patients suspected of contracting SARS should include chest x-ray film, blood cultures, sputum cultures and Gram stain, pulse oximetry, and identification of other potential pathogens, including influenza A and B, Legionella, and RSV. For unclear reasons, SARS appears to be less severe for pediatric patients.

Tuberculosis

The acid-fast bacillus M. tuberculosis causes tuberculosis and is spread person to person by inhalation of droplets. After years of steady decline, the number of cases of pneumonia caused by M. tuberculosis in the United States began to increase in the middle to late 1980s. The new epidemic was a consequence of an increased incidence among prison inmates, IV drug abusers, immigrants, and, most prominently, HIV-infected patients.75 It is most prominent in urban neighborhoods afflicted with crowded conditions and poor access to healthcare. Unlike previous eras in which tuberculosis was seen most frequently in elderly men, infection currently is identified in increasing numbers of young minority adults. As mentioned, the resurgence of tuberculosis is at least partially related to coinfection with HIV; HIV-infected patients are more likely to develop symptomatic disease with its associated fits of coughing than are their immunocompetent counterparts, and this enables further spread of infection. Other groups prone to tuberculosis include the homeless and patients in chronic care facilities and homes for the elderly. Fortunately, since 1992, the incidence of tuberculosis in the United States has declined, reaching a record low. However, the incidence of tuberculosis worldwide continues to increase. Both the sustained worldwide increase in tuberculosis and the reemergence of tuberculosis in the United States are important reasons for the development of multiple-drug resistance, that is, mycobacteria that are resistant to two or more of the first-line antituberculosis drugs. Infection caused by these organisms is poorly responsive to alternative therapy and is associated with mortality rates exceeding 50% (see Chap. 90 for a detailed discussion on the diagnosis and treatment of tuberculosis).

TREATMENT

Desired Outcome

Eradication of the offending organism through selection of the appropriate antibiotic and complete clinical cure are the goals of therapy for bacterial pneumonia. Therapy should minimize associated morbidity, including one or both of the following: reversible or irreversible disease and drug-induced organ toxicity (e.g., renal, lung, or hepatic dysfunction). Most cases of viral pneumonia are self-limiting, although therapy of influenza pneumonia with specific antiviral agents (oseltamivir and zanamivir) may hasten recovery. All efforts should focus on the design of the most cost-effective approach to therapy. Whenever possible, the oral (vs. parenteral) route for drug administration should be selected, encouraging outpatient management rather than hospitalization.

General Approach to Treatment

Images The first priority in assessing the patient with pneumonia is to evaluate the adequacy of respiratory function and to determine the presence of signs of systemic illness, specifically dehydration or sepsis with resulting circulatory collapse. Oxygen or, in severe cases, mechanical ventilation and fluid resuscitation should be provided as necessary. Further supportive care of the patient with pneumonia includes humidified oxygen for hypoxemia, administration of bronchodilators (albuterol) when bronchospasm is present, and chest physiotherapy with postural drainage if evidence of retained secretions is present. Additional therapeutic adjuncts include adequate hydration (IV if necessary), optimal nutritional support, and control of fever. Appropriate sputum samples may be obtained to determine the microbiologic etiology. Rehydration should be provided to replace losses that may have occurred as a result of fever, poor intake, and/or associated vomiting. Selection of an appropriate antimicrobial must be made based on the patient’s probable or documented microbiology, distribution in the respiratory tract, side effects, and cost. Respiratory tract infection diagnosis and treatment guideline reports have been published by authoritative professional organizations that focus on proper treatment regimens and should be consulted for evidence-based treatment recommendations across the spectrum of community- and/or hospital-associated pneumonias.76,77


Clinical Controversy…

Various adjunctive therapy options have been studied for their potential benefits in CAP in recent years. Drugs that have been studied include corticosteroids, prostaglandin inhibitors, statins, immunoglobulin therapy, mediator-specific immunomodulators, angiotensinogen-converting enzyme inhibitors, and oral hypoglycemic agents. Proposed mechanisms for some of the drugs have centered on protective effects (e.g., vasodilation, cough reflex) and antiinflammatory effects. Differences in study design and patient populations have made it difficult to determine if there are any true benefits these therapies may have in CAP.78

Pharmacologic Therapy

Antibiotic Concentrations

Antibiotic concentrations in respiratory secretions in excess of the pathogen MIC are necessary for successful treatment of pulmonary infections.77 The concept of a blood–bronchus barrier, analogous but dissimilar to the blood–brain barrier, has been used to assess the characteristics of drug penetration into pulmonary secretions. The ability of a drug to penetrate respiratory secretions depends on multiple physicochemical factors, including molecular size, lipid solubility, and degree of ionization at serum and biologic fluid pH and extent of protein binding. Studies performed in animals and cystic fibrosis patients suggest that larger molecular size favors the accumulation of drugs in bronchial secretions. This finding contrasts with data on drug penetration of other physiologic compartments, such as the cerebrospinal fluid, and may be a result of the trapping of lower-molecular-weight compounds in mucin pores. Nevertheless, the rate at which a drug may accumulate in certain respiratory secretions appears to remain an important factor relative to the drug’s clinical efficacy in treating pulmonary infections. The unionized form of drug and lipid solubility also appears to favor drug penetration. Of note, the pH of the infected bronchi often is more acidic than that of normal tissue and blood. These factors combined underscore the importance of considering the inhaled route of antimicrobial drugs for the treatment of patients with moderate to severe pneumonia, particularly in high-risk patient groups.79,80


Clinical Controversy…

Prior to the availability of newer β-lactam and fluoroquinolone antibiotics possessing consistently potent activity against multiple gram-negative pathogens, some investigators promoted the administration of antibiotics by direct endotracheal instillation. This method of drug administration attempts to provide increased topical concentrations of antibiotics that do not appear to penetrate respiratory secretions effectively while reducing the likelihood of systemic toxicity. In addition, greater local concentrations of antibiotics, particularly of the polymyxins and aminoglycosides, are believed to overcome partially the substantial decrease in antibiotic bioactivity observed when these agents interact with the purulent material present in infectious foci. Despite these potential theoretical advantages, the role of antibiotic aerosols or direct endotracheal instillation in clinical practice remains controversial and guidelines do not recommend the routine use of aerosolized antibiotics.7,77,7981

Limited data are available for assessing the influence of drug protein binding on the rate and amount of respiratory secretion penetration. Clearly, it is the free antibiotic fraction reaching the infected site capable of binding to the bacterial cell target that is responsible for antibacterial activity. Given that the degree of protein binding influences a drug’s ability to traverse membranes, a similar relationship would be expected within the lung. However, focusing on the absolute amount of an antibiotic bound to plasma/tissue proteins without accounting for the drug’s overall antibacterial potency is errant. To completely assess an antibiotic’s therapeutic potential in the treatment of pneumonia or any infectious process, it is prudent to assess the antibiotic’s integrated pharmacokinetic–pharmacodynamic (PK-PD) characteristics (e.g., bacterial killing may be concentration dependent or time dependent) that account for the drug’s degree of binding to serum proteins, tissue distribution, and in vitro potency. These concepts relating to antibiotic activity and overall drug penetration of respiratory secretions underscore the importance of applying the advances realized in our knowledge of antimicrobial PK and PD to the design of optimal antibiotic dosing regimens. Integration of an individual antimicrobial drug’s PK-PD has afforded the development of just such optimal antibiotic dosing regimens (improved efficacy and safety) based on drug- and patient-specific factors.76,77 A primary example of antibiotic PK-PD–designed optimal dosing is reflected in the clinical practice of administering certain antibiotics (aminoglycosides) to achieve high peak serum concentrations on the assumption that higher (and possibly more effective) biologic fluid concentrations of the drug will be achieved. The aminoglycosides are large polar molecules that diffuse poorly into tissue and respiratory secretions; however, with increasing concentrations obtained with once-daily dosing, increased target-tissue concentrations would be expected with increasing individual doses. Further, recognizing that the peak drug concentration-to-pathogen MIC ratio (Cmax:MIC) is the primary PK-PD correlate for aminoglycosides and that the target Cmax:MIC ratio for aminoglycosides is ~10, the single daily dose strategy is most likely to achieve the desired PK-PD target at the desired anatomic site. Similar is the case for the so-called respiratory fluoroquinolones (e.g., levofloxacin, moxifloxacin, gemifloxacin) higher individual dose therapy targeting a greater Cmax:MIC ratio or the more commonly targeted area under the concentration–time curve (AUC)-to-pathogen MIC ratio, that is, AUC:MIC, for fluoroquinolones. The target 24-hour AUC:MIC ratio for fluoroquinolones is >35 (possible minimum of 25) for gram-positive and >125 (possible minimum of 100) for gram-negative pathogens. For greatest probability of success, the antibiotic concentrations projected in these PK-PD correlates should include the expected free (not protein-bound) antibiotic concentration. Conversely, concentration-dependent killing characteristics best correlate with successful therapy with the β-lactam/carbapenem and macrolide classes of antimicrobials.76,77 See eChapter 24 and Chapter 83 for more in-depth discussion of antibiotic concepts.

Sputum is frequently assessed as possibly representing the PD interface for pulmonary infections. It is only one of many pulmonary fluids and secretions, and it may serve as a reservoir for pathogen growth. These beliefs have led many investigators to assess antibiotic concentrations in sputum, frequently describing sputum drug concentrations as a ratio of serum to sputum drug concentration. Although sputum drug concentrations provide some insight into the characteristics of drug penetration of respiratory secretions, caution should be exercised in the interpretation of these data. Data describing sputum drug concentrations often are difficult to interpret because of differences in analytic techniques, method of sputum sampling, and random nature of sampling times relative to drug dose. Moreover, representation of sputum drug concentrations as a ratio of serum drug concentration can be misleading and most probably should be described relative to absolute drug concentration or apparent area under the drug concentration versus time curve in sputum. To more accurately describe the distribution characteristics of antimicrobial agents in sputum, research studies should be designed to allow sequential repeated sputum sampling over a specified dosage interval under both first-dose and steady-state conditions. Thus, until greater sophistication is achieved in our understanding of the relationships between antibiotic concentrations in specific anatomic sites, plasma (blood)-based integrated PK-PD correlates should be used for antibiotic and dose selection.

Selection of Antimicrobial Agents

Treatment of bacterial pneumonia, like the treatment of most infectious diseases, initially involves the empirical use of a relatively broad-spectrum antibiotic that is effective against probable pathogens after appropriate cultures and specimens for laboratory evaluation have been obtained.5,7,81 Therapy should be narrowed to cover specific pathogens after the results of cultures are known. Multiple factors that help to define the potential pathogens involved include patient age, previous and current medication history, underlying disease(s), major organ function, and present clinical status. These factors must be evaluated to select an appropriate and effective empirical antibiotic regimen as well as the most appropriate route for drug administration (oral or parenteral). For a more detailed discussion on the principles of antibiotic selection, see Chapter 83.

Numerous antibiotics are available, and many are effective in the treatment of bacterial pneumonia. Superiority of one antibiotic over another when both demonstrate similar dose-normalized in vitro activity and tissue distribution characteristics is difficult to define. Our opinions on appropriate empirical choices for the treatment of bacterial pneumonias relative to a patient’s underlying disease are listed in Table 85–8 for adults and Table 85–9 for children. A complete listing of antimicrobial agents for specific pathogens is beyond the scope of this chapter and is presented in Chapter 83.

TABLE 85-8 Evidence-Based Empirical Antimicrobial Therapy for Pneumonia in Adultsa

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TABLE 85-9 Empirical Antimicrobial Therapy for Pneumonia in Pediatric Patientsa

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A patient’s medical history of responding/not responding to one of these antibiotics in the recent past will assist greatly in the decision to continue their use. In contrast and for patients with risk factors, regardless of the patient’s setting at the time of infection, that is, community, long-term care facility, acute care hospital, etc., the fluoroquinolone antibiotics represent important treatment tools based on their highly favorable PK (tissue and intracellular distribution) and PD (potency, broad spectrum) characteristics combined with ease of administration (IV, oral) and patient tolerability. Furthermore, optimal dosing directed by the projected 24-hour free fluoroquinolone AUC-to-pathogen MIC ratio (see above) has markedly decreased the emergence of pathogen resistance, fostered maximal bacteriologic kill, and enhanced patient safety.

Table 85–10 lists dosages for selected antibiotics used for the treatment of bacterial pneumonia. The large number of expensive drugs mandates critical evaluation for formulary selection and clinical use. Similarities of in vitro activity, resistance to bacterial-inactivating enzymes, and overall effectiveness often make rational therapeutic decisions difficult and even appear random. However, some general principles can be applied to guide rational antibiotic choice, including direct comparison of the antibiotic’s likely attainment of the defined PK-PD target correlate for specific bacterial species within the infected site. An understanding and application of inherent drug characteristics appears to be of the utmost importance for the selection of an optimal therapeutic regimen. Thus, whenever possible, identification of the causative pathogen and expected/defined antibiotic activity (e.g., MIC) is of paramount importance to the selection/design of the optimal antibiotic regimen.

TABLE 85-10 Antibiotic Doses for Treatment of Bacterial Pneumonia

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Community-Acquired Pneumonia

Tables 85–8 and 85-9 provide evidence-based guidelines for the treatment of CAP in adults5 and children,6 respectively. The bacterial causes are relatively constant, even across geographic areas and patient populations. Unfortunately, pathogen resistance to standard antimicrobials is increasing (e.g., penicillin-resistant pneumococci), necessitating careful attention by the clinician to local and regional bacterial susceptibility patterns.50 Thus, whenever possible, initial therapy should be based on presumed antibacterial susceptibility and consist of older, less-expensive agents, with newer and more expensive antibiotics reserved for unresponsive illness or special circumstances. Indiscriminate use of recently introduced agents increases healthcare costs and, in some instances (e.g., widespread use of fluoroquinolones), induces resistance among a significant percentage of community-acquired organisms.5 The rapidly evolving epidemiology of bacterial resistance, including the increasing emergence of penicillin-resistant S. pneumoniae in many areas of the United States and Europe, forces the clinician to be vigilant and knowledgeable about antibiotic sensitivity patterns in each community. Indiscriminate use of antimicrobials for treatment of pneumonia has contributed to the problem of antimicrobial resistance, underscoring the need for defining the optimal antibiotic regimen for each patient.

Images Evidence-based empirical therapy differs among outpatients, hospitalized patients, and hospitalized patients admitted to an intensive care unit (Tables 85–8 and 85-9).5,6 Antimicrobial therapy should be initiated for hospitalized patients with acute pneumonia within 8 hours of admission because an increase in mortality has been demonstrated when therapy was delayed beyond 8 hours of admission.

Healthcare-Associated Pneumonia

It is important to identify patients at risk for HCAP and initiate appropriate empirical antibiotic therapy since these patients are at risk for MDR organisms. Delaying treatment of appropriate antibiotics in these patients increases mortality.51 Antibiotic selection will be similar to those used in HAP and VAP. Broad-spectrum antibiotics should be used empirically for pneumonia developing ≥5 days after hospital admission or if the patient has risk factors for MDR pathogens.7 See Table 85–8 for recommended empirical antimicrobial therapy.

Hospital-Acquired Pneumonia

Images Antibiotic selection within the hospital environment demands greater care because of constant changes in antibiotic resistance patterns in vitro and in vivo. Ironically, some β-lactam antibiotics, which were developed to treat MDR hospital-acquired organisms, can themselves induce broad-spectrum bacterial β-lactamases and thereby lead to even greater problems with resistance.77 These facts underscore the importance of regularly documenting the epidemiology of pathogens and infectious diseases within a specific practice or institution. As a result, an antimicrobial agent for a specific infectious disease favored in one practice site may not be the most desirable selection in another site despite similarities in size and patient profile. Strict and careful control and, possibly, rotation of empirical antibiotics in the hospital environment may help to limit the emergence of resistant organisms. Newer antibiotics developed for treatment of resistant, hospital-acquired pathogens are costly; therefore, their use must be moderated to some extent in an era where capitated hospital costs and mandated budget cuts will not tolerate careless antibiotic use. Broad-spectrum antibiotics are more appropriate choices for patients with risk factors for MDR pathogens or if HAP develops after at least 5 days of hospitalization.7 See Table 85–8 for recommended antimicrobial therapy.

Ventilator-Associated Pneumonia

The approach to treating VAP is similar to antibiotic selection in HAP and HCAP (see Table 85–8). Patients should be carefully evaluated to determine whether they are at risk for MDR pathogens as this is essential in selecting appropriate empirical antibiotic therapy.7 It is also important to identify patients with VAP early since delays in initiating appropriate antibiotic therapy are associated with increased mortality. Aerosolized antibiotic delivery has been considered for more targeted therapy; however, there are limited studies at this time supporting the safety and efficacy in pneumonia.82

Atypical Pneumonia

Pneumonia caused by atypical pathogens may be more difficult to treat with antibiotics than “typical” pathogens. It is debatable whether empirical treatment for hospitalized patients with CAP should include antibiotic coverage of atypical pathogens; however, if patients present with extrapulmonary findings, atypical coverage should be given higher consideration.67 There does not appear to be any benefit in terms of survival or clinical efficacy to providing atypical coverage for all patients.83 See Table 85–8 for a summary of the evidence-based guidelines on management.

For Legionella pneumonia, respiratory fluoroquinolones and doxycycline are superior to macrolides, the previous drug of choice.84 Double antibiotic coverage is not recommended if one of these agents is used unless the patient is immunocompromised.67 Mycoplasma pneumonia is difficult to treat due to the organism’s lack of a cell wall, limiting certain antibiotics, and it is found on epithelial cells in the respiratory tract instead of inside the cells.52,67Macrolides and tetracyclines are generally effective against Mycoplasma; however, macrolide-resistant strains have been emerging over the past decade.68Chlamydophila organisms are sensitive to macrolides, doxycycline, and fluoroquinolones. Symptoms such as cough and malaise may be present for months following antibiotic therapy.52 The management of tuberculosis is further discussed in Chapter 90.

For viral causes of pneumonia, antivirals such as amantadine and oseltamivir can be used, depending on viral susceptibility. Treatment for H5N1 and H1N1 is primarily supportive; patients with H5N1 generally require aggressive oxygen therapy and intensive monitoring70,71 while the majority of those with H1N1 are treated as outpatients. Both viruses are resistant to amantadine; therefore, the neuraminidase inhibitors oseltamivir and zanamivir are recommended if antivirals are administered. Treatment of SARS involves primarily supportive care and procedures to prevent transmission to others.73Owing to the uncertainty associated with the diagnosis of SARS, empirical therapy with broad-spectrum antibiotics should be used including fluoroquinolones or macrolides/azalides. Although its efficacy is unproven, ribavirin also has been used to treat patients and corticosteroids have been used owing to the potential benefit in the presence of progressive pulmonary disease; methylprednisolone has been used in doses ranging from 80 to 500 mg/day.

Prevention

Prevention of some cases of pneumonia is possible through the use of vaccines and medications against selected infectious agents. Polyvalent polysaccharide vaccines are available for two of the leading causes of bacterial pneumonia, S. pneumoniae and H. influenzae type b. Children should be vaccinated against S. pneumoniaeH. influenzae type b, pertussis, and influenza; immune prophylaxis for RSV is recommended for high-risk infants during RSV season. Caregivers for infants <6 months should also be vaccinated against influenza and pertussis. To minimize the risk of developing VAP, healthcare providers should seek to minimize colonization of the aerodigestive tract, prevent aspiration (head raised 45°), and limit the length of mechanical ventilation.66 In addition, evidence-based guidelines for preventing HCAP have been published (Table 85–11).85 (See Chap. 87 for a full discussion of prevention of influenza and Chap. 102 for vaccines.)

TABLE 85-11 Evidenced-Based Guidelines for Preventing Healthcare-Associated Pneumonia

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EVALUATION OF THERAPEUTIC OUTCOMES

After therapy has been instituted, appropriate clinical parameters should be monitored to ensure the efficacy and safety of the therapeutic regimen. For patients with bacterial infections of the upper or lower respiratory tract, the time to resolution of initial presenting symptoms and the lack of appearance of new associated symptomatology are important to determine. For patients with CAP or pneumonia from any source of mild to moderate clinical severity, the time to resolution of cough, decreasing sputum production, and fever, as well as other constitutional symptoms of malaise, nausea, vomiting, and lethargy, should be noted. If the patient requires supplemental oxygen therapy, the amount and need should be assessed regularly. A gradual and persistent improvement in the resolution of these symptoms and therapies should be observed. Initial resolution should be observed within the first 2 days and progression to complete resolution within 5 to 7 days but usually no more than 10 days.

For patients with HAP/HCAP, substantial underlying diseases, or both, additional parameters can be followed, including the magnitude and character of the peripheral blood WBC count, chest radiograph, and blood gas determinations. Similar to patients with less severe disease, some resolution of symptoms should be observed within 2 days of instituting antibiotic therapy. If no resolution of symptoms is observed within 2 days of starting seemingly appropriate antibiotic therapy or if the patient’s clinical status is deteriorating, the appropriateness of initial antibiotic therapy should be critically reassessed. The patient should be evaluated carefully for deterioration of underlying concurrent disease(s). Additionally, the caregiver should consider the possibility of changing the initial antibiotic therapy to expand antimicrobial coverage not included in the original regimen (e.g., MycoplasmaLegionella, and anaerobes). Furthermore, the need for antifungal therapy (lipid-based amphotericin B) should be considered. Some resolution of symptoms should be observed within 2 days of starting proper antibiotic therapy, with complete resolution expected within 10 to 14 days.

ABBREVIATIONS

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