Pneumonia and Other Pulmonary Infections Part 2

Differential diagnosis

Noninfectious diseases can be mistaken for infections of the respiratory tract. Asthmatic bronchitis and hypersensitivity pneumonitis are common examples. COPD, including emphysema and bronchiectasis, may be misleading if previous x-rays are not available. Atelectasis, pulmonary infarction, pulmonary edema, and lung tumors may also be confused with pneumonia. Hypersensitivity reactions and toxins—in the form of aerosols, systemic drugs, or chemicals—produce clinical illnesses and pulmonary infiltrates simulating those of infectious pneumonia. Radiation pneumonitis, sarcoidosis, vasculitis, ure-mic pneumonitis, pulmonary hemorrhage, eosinophilic pneumonia, organizing pneumonia, and lipoid pneumonitis are included in the differential diagnosis [see 14:V Chronic Diffuse Infil-trative Lung Disease].

One of the primary considerations in patients with a lower respiratory tract infection is to distinguish between acute bronchitis and pneumonia. The distinction is anatomic rather than etiologic because the same basic range of organisms can cause the two syndromes. As a result, these conditions often overlap clinically, but bronchitis requires less intensive therapy [see Acute Bronchitis, below].

Treatment

Certain general principles are useful in the care of all patients with pneumonia. Adequate hydration is important to help clear secretions; hydration can be achieved by systemic administration of fluids and local airway humidification. Expectorants such as guaifenesin may be helpful in loosening the sputum. Although clinical trials have demonstrated that chest physiotherapy does not hasten the resolution of pneumonia, this traditional therapeutic modality may provide symptomatic benefit to patients with copious airway secretions. In general, the cough reflex should not be suppressed in patients with bacterial infections, because coughing is an important mechanism for clearing secretions. If severe paroxysms of coughing produce respiratory fatigue or harsh pain, however, temporary relief may be obtained with small doses of codeine. Chest pain should be treated with analgesics that do not suppress cough. If hypoxia is present, oxygen should be administered. Persons who have COPD and retain carbon dioxide must be monitored very closely because oxygen therapy can lead to respiratory depression.

Specific antimicrobial therapy depends on the etiologic agent. Whereas culture and sensitivity testing require at least 24 to 48 hours to provide definitive information, the clinical setting, chest x-ray, and sputum Gram stain usually enable the physician to make a reasonable presumptive diagnosis and to initiate therapy at once. Treatment can then be modified as necessary on the basis of culture results. Because antibiotics penetrate sputum by passive diffusion, it is important to maintain adequate blood levels of these drugs. The administration of antibiotics by aerosol is not indicated for most cases of pneumonia but may help patients with cystic fibrosis and endobronchial Pseudomo-nas infections.41

Table 3 Initial Antibiotic Therapy for Community-Acquired Pneumonia in Outpatients*

Drug	Typical Dosef	Cost/Mo ($)i	Comments
Fluoroquinolones			Excellent first-line drugs
Levofloxacin	500 mg p.o., q. 24 hr for 10 days, or 750 mg p.o., q. 24 hr for 5 days	279
Gatifloxacin	400 mg p.o., q. 24 hr	252
Moxifloxacin	400 mg p.o., q. 24 hr	265
Gemifloxacin	320 mg p.o., q. 24 hr	NA
Macrolides
Erythromycin	250-500 mg p.o., q. 6 hr	34	Cost-effective alternative, but GI intolerance is common
Clarithromycin	250-500 mg p.o., q. 12 hr	235	Better GI tolerability and activity against Haemophilus and Moraxella; good first-line drug
Azithromycin	500 mg p.o. day 1, then 250 mg p.o. days 2-5	NA	Better GI tolerance and activity against Haemophilus and Moraxella
Doxycycline	100 mg p.o., q. 12 hr	92	Cost-effective alternative

*See text for details.

+For details, Chemotherapy of Infection (especially Tables 3 and 4).

iCosts are derived from online pharmaceutical sources and are intended to indicate relative costs of available therapies. GI—gastrointestinal

Table 4 Initial Antibiotic Therapy for Community-Acquired Pneumonia in Patients Who Require Hospitalization*

Regimen	Typical Dose+	Cost/Mo ($)*	Comments
Cephalosporins Cefotaxime or ceftriaxone + a macrolide+ or a fluoroquinolone+	Cefotaxime, 1-2 g I.V. q. 4 hr; ceftriaxone, 1-2 g I.V. q. 12-24 hr	—	First-line treatment of choice for severely ill patients
Fluoroquinolones Levofloxacin Moxifloxacin Gatifloxacin	500 mg p.o. or I.V. q. 24 hr 400 mg p.o. or I.V. q. 24 hr 400 mg p.o. or I.V. q. 24 hr	279 265 252	First-line treatment, either alone or with a third-generation cephalosporin
Vancomycin + a macrolide§ or a fluoroquinolone+	Vancomycin, 1 g I.V. q. 12 hr	—	Alternative for severely ill patients who are allergic to p-lactams
Linezolid + a macrolide* or a fluoroquinolone+	Linezolid, 600 mg p.o. or I.V. q. 12 hr	3,308	For severely ill patients who cannot tolerate p-lactams or vancomycin

*See text for details.

^For details, Chemotherapy of Infection (especially Tables 3 and 4).

§For macrolide doses, see Table 3; azithromycin may be administered intravenously.

*Costs are derived from online pharmaceutical sources and are intended to indicate relative costs of available therapies. 

It is best to choose an antibiotic regimen directed specifically at organisms seen on Gram stain and, after 24 to 48 hours, identified from sputum or blood cultures. Even if these data are lacking, however, a reasonable choice of initial antimicrobial therapy can be made on the basis of the epidemiologic setting and clinical features.

Community-Acquired Pneumonia

Several factors are responsible for rapid changes in the empirical treatment of community-acquired pneumonias: the emergence of drug-resistant pneumococci; the increasing population of elderly or chronically ill patients who are vulnerable to infections caused by H. influenzae and M. catarrhalis; the increased importance of atypical pathogens such as M. pneumoniae, C. pneu-moniae, and L. pneumophila; and the availability of new fluoro-quinolones with enhanced activity against gram-positive cocci (including penicillin-nonsensitive pneumococci) and anaerobes (including mouth flora). For patients who do not require hospitalization, several options are available [see Table 3].42 Eryth-romycin is cost-effective, but the so-called advanced macro-lides clarithromycin and azithromycin may be preferable because of their better gastrointestinal tolerability and their activity against Haemophilus and Moraxella species.43-45 Doxycycline is an effective and inexpensive alternative.46 However, because of the increasing prevalence of drug-resistant pneumococci, use of one of the so-called respiratory fluoroquinolones (i.e., lev-ofloxacin, gatifloxacin, moxifloxacin, or gemifloxacin) is recom-mended.47 These agents have excellent activity against the major causes of community-acquired pneumonia, and prospective trials have been very favorable.47,48 They are a particularly good choice for patients who have recently received antibiotic thera-py.49 The use of high-dose levofloxacin (750 mg a day) may enable short-course (5-day) therapy, potentially improving compliance and reducing costs.50 The respiratory fluoroquinolones may also emerge as drugs of choice for patients with community-acquired pneumonia who require hospitalization; lev-ofloxacin, moxifloxacin, and gatifloxacin are available in preparations for intravenous administration [see Table 4]. Lev-ofloxacin-resistant pneumococci are still uncommon, but their emergence is a concern.51,52 In addition, dual therapy may be preferable for patients with severe pneumococcal pneumonia.53,54 For that reason, patients with moderate to severe community-acquired pneumonia may benefit from cefotaxime or ceftriax-one in combination with a macrolide or a fluoroquinolone.42 Because vancomycin is active against virtually all pneumococci, it can be substituted for the third-generation cephalosporin in patients allergic to ^-lactams; linezolid is another alternative.55 When aspiration is suspected, penicillin, clindamycin, or metro-nidazole is useful; amoxicillin-clavulanate, imipenem, meropen-em, and respiratory fluoroquinolones are also active against oral anaerobes [see Table 5].

In all cases, antibiotic therapy should be tailored to the results of culture and sensitivity, the clinical response, and the occurrence of side effects. Many patients who require intravenous antibiotics initially can be switched to oral therapy within 3 days,56 facilitating early hospital discharge.57 In most patients with uncomplicated pneumococcal pneumonia, antibiotics can be discontinued after 3 afebrile days; most patients with other bacterial pneumonias are treated for 7 to 14 days, and most with atypical pneumonias are treated for 10 to 21 days.

Immunizations may help prevent community-acquired pneumonia. Each fall, influenza vaccine should be offered to patients 50 years of age and older and to other vulnerable persons [see 7:XXV Respiratory Viral Infections]. Pneumococcal polysaccharide vaccine should be offered to persons 65 years of age and older and to others who are at increased risk58 [see 7:I Infections Due to Gram-Positive Cocci]. Patients who have recovered from one bout of pneumonia may benefit from both vaccines.

Table 5 Antibiotic Choices for Aspiration Pneumonia*

Drug	Typical Dosef	Cost/mo ($)-	Comments
Penicillin	500 mg p.o., q. 6 hr, to 1-2 million units I.V. q. 4 hr, depending on severity of infection	22	Traditional drug of choice
Clindamycin	150-300 mg p.o., q. 6 hr, to 600 mg I.V. q. 8 hr, depending on severity of infection	318	May be superior to penicillin
Metronidazole	500 mg p.o., q. 8 hr, to 500 mg I.V. q. 6 hr, depending on severity of infection	28	Excellent alternative
Ampicillin-sulbactam	1-2 g ampicillin + 0.5-1 g sulbactam I.V. q. 6 hr		Alternative useful in hospitalized patients
Imipenem	0.5-1 g I.V. q. 6-8 hr		Alternative useful in hospitalized patients
Meropenem	1 g I.V. q. 8 hr		Alternative useful in hospitalized patients
Fluoroquinolones
Gatifloxacin	400 mg p.o. or I.V. q. 24 hr	252	Excellent for community-acquired pneumonias but less active against oral anaerobes than penicillin, clindamycin, and metronidazole
Moxifloxacin	400 mg p.o. or I.V. q. 24 hr	265
Levofloxacin	500 mg p.o. or I.V. q. 24 hr	279

*See text for details.

+For details, Chemotherapy of Infection (especially Tables 3 and 4).

-Costs are derived from online pharmaceutical sources and are intended to indicate relative costs of available therapies.

Hospital-Acquired Pneumonia

Because gram-negative bacilli and S. aureus cause many noso-comial pneumonias, patients with hospital-acquired pneumonias require broad antimicrobial coverage until the results of Gram stains, cultures, and sensitivity tests permit focused therapy. Options for the initial treatment of hospital-acquired pneumonia include ticarcillin-clavulanate or piperacillin-tazobactam; meropenem or imipenem-cilastatin; a third-generation cephalo-sporin plus nafcillin or vancomycin; a first-generation cephalo-sporin plus an aminoglycoside; or vancomycin plus an amino-glycoside. The prevalence of resistant bacteria in a particular hospital or patient care unit should help guide the initial therapy; for example, if methicillin-resistant staphylococci are common, vancomycin is a desirable component of the initial therapy, and when multidrug-resistant Klebsiella organisms are common, meropenem or imipenem-cilastatin should be considered. Linezolid is an effective alternative to vancomycin for the treatment of nosocomial pneumonia caused by methicillin-resistant gram-positive cocci. Patients with ventilator-associated nosoco-mial pneumonia may respond as well to 8 days of antibiotics as to 15 days of therapy.59 Because of the high mortality associated with pneumonias in the ICU, strategies to prevent them have been studied,60 and comprehensive guidelines are available.61

Infections Caused by Legionella Species

Legionnaires disease

Epidemiology and Etiology

Since it was first identified in 1976, Legionnaires disease has become recognized as a common cause of both community-acquired and hospital-acquired pneumonias. Worldwide, it accounts for between 2% and 15% of all community-acquired pneumonias severe enough to require hospitalization.62 It is estimated that 10,000 to 25,000 cases occur in the United States each year, but only 1,200 to 1,500 are reported annually.63 Legionnaires disease is caused by L. pneumophila, a fastidious, filamentous, flagellated, aerobic gram-negative bacillus. The organism can be grown on charcoal-yeast extract agar; optimal growth occurs at 35° C in 5% carbon dioxide, but growth is slow, and a period of 3 to 6 days is required for colonies to form.

At least nine serogroups of L. pneumophila exist; most clinical isolates belong to serogroup 1. By special staining techniques, large numbers of the organism can be identified in tissue sections of alveoli, both within macrophages and extracellularly. Virulence factors of L. pneumophila and various extracellular enzymes that the organism secretes have been identified. L. pneu-mophila is able to survive intracellularly in host leukocytes. Antibody is not protective, but cell-mediated immunity does promote recovery and prevent reinfection.

In nature, L. pneumophila survives principally in water and, to a lesser extent, in soil. Human disease is acquired primarily by inhalation of aerosols contaminated with organisms; person-to-person transmission has not been documented. Contaminated water systems have been responsible for both community-acquired and hospital-acquired outbreaks [see 7:X Infections Due to Haemophilus, Moraxella, Legionella, Bordetella, and Pseudomonas].

The attack rate for Legionnaires disease appears to be higher in elderly persons and persons with underlying conditions such as COPD, neoplastic disease, organ transplants, and renal failure. Although L. pneumophila is a relatively uncommon pathogen in persons infected with HIV, it can cause severe disease in them.

Diagnosis

Clinical features Legionnaires disease is characterized by a 1-day prodrome of myalgias, malaise, and slight headache after an incubation period of 2 to 10 days. Acute onset of high fever, shaking chills, nonproductive cough, tachypnea, and, often, pleuritic pain ensues. The cough may subsequently become slightly productive, but the sputum is not purulent. Obtunda-tion or toxic encephalopathy is common, but frank meningitis is not a feature. Abdominal pain, vomiting, and, especially, diarrhea may be present. Signs of consolidation on lung examination are present infrequently, but rales are commonly heard. Chest radiographs show patchy or interstitial infiltrates, which often progress to areas of nodular consolidation in a single lobe or multiple lobes; minimal effusions are present in up to one third of cases. Abscess formation is uncommon but has been observed. Pulmonary fibrosis may occur in some survivors.

Although pneumonia is present in nearly all patients with Legionnaires disease, extrathoracic symptoms can be the presenting or predominant features. Central nervous system, GI, and renal manifestations are especially common. L. pneumophila has been isolated from blood cultures, and the organism can be found in many organs both in immunosuppressed patients and in previously normal patients who are afflicted with severe disease. Extrapulmonary manifestations include ocular and peri-cardial involvement, perirectal abscess, wound infection, peritonitis, cellulitis, rhabdomyolysis and acute renal failure, neu-tropenia, hemolytic anemia, and thrombotic thrombocytopenic purpura. Implanted devices such as heart valves and hemodial-ysis fistulas can become colonized.

A nonpneumonic form of legionellosis called Pontiac fever has a short incubation period and a low mortality. It has been responsible for at least four outbreaks of illness, including several related to whirlpools and hot tubs.

Laboratory studies The peripheral white blood cell count is mildly elevated to between 8,000 and 16,000/mm3. Cold agglutinins are negative. Other laboratory findings may include an elevated erythrocyte sedimentation rate, hypoxia, abnormal liver function test results, and elevated creatine phosphokinase levels.64 Proteinuria and microscopic hematuria have been observed, and acute renal failure may complicate the course on occasion.

Gram stains of the sputum or tracheal secretions will not reveal L. pneumophila, but the organism can be isolated from sputum and other specimens by using charcoal-yeast extract agar. The diagnosis can be established rapidly in about 20% of cases by demonstrating the organism with direct immunofluorescent staining of sputum specimens; bronchoalveolar lavage may be helpful in immunosuppressed patients. A kit that uses radiola-beled complementary DNA is commercially available, but clinical experience is still limited. A very promising polymerase chain reaction assay has been developed.65

Another method of rapid diagnosis involves detection of L. pneumophila antigen in the urine; this radioimmunoassay test is highly specific and has a sensitivity of about 80% to 90%.® However, the test is available only for L. pneumophila serogroup 1, which is the most common cause of Legionnaires disease. Most often, however, the diagnosis is established by an indirect fluorescent antibody technique involving staining of the causative bacterium. With this technique, a fourfold or greater rise in titer during the illness or a stable titer of 1:256 or greater is considered diagnostic.

The clinical picture and radiologic findings in Legionnaires disease are not specific. The diagnosis should be considered in patients with segmental, lobar, or interstitial pneumonia in which the etiologic agent is not evident on Gram stains of sputum or tracheal secretions. A mild case may resemble Mycoplas-ma pneumonia or other types of atypical pneumonia.

Treatment

On in vitro susceptibility testing, L. pneumophila has been shown to be susceptible to a variety of antimicrobial agents, including erythromycin, clarithromycin, azithromycin, tetracy-cline, rifampin, and the fluoroquinolones. Current evidence indicates that azithromycin66 or levofloxacin is the treatment of choice.67 Occasionally, patients may experience a relapse if antibiotics are discontinued prematurely; recovery occurs during a second, more prolonged course of treatment. A combination of rifampin and either azithromycin or levofloxacin may be considered in patients who fail to respond to monotherapy and in immunologically impaired patients with overwhelming disease. Improvements in diagnosis and therapy have produced a dramatic decline in the case-fatality rate of L. pneumophila infection, from 34% in 1980 to 12% in 1998.