Sulbactam

Community-acquired pneumonia (CAP) affects approximately 4.5 million adults in the United States annually. (1) About one third of these adults require hospitalization. (1) The mortality rate among hospitalized patients with CAP varies each year and can reach 35 percent. (2) While Streptococcus pneumoniae causes up to 70 percent of CAP cases, atypical pathogens are responsible for 30 to 40 percent of cases (3) and may be copathogens in other cases. Even with a knowledge of some of the common characteristics of infections with atypical organisms (Table 1), (4) determining the specific pathogen on the basis of clinical, radiologic, and laboratory findings is difficult and usually done retrospectively, if at all.

Atypical Pathogens

MYCOPLASMA PNEUMONIAE

Mycoplasma pneumoniae causes a wide range of respiratory infections, including pneumonia, tracheobronchitis, and upper respiratory tract infection. Only 3 to 10 percent of persons infected with M. pneumoniae develop pneumonia. (5) Because M. pneumoniae infection becomes more common with increasing age, it is particularly important to consider this agent in elderly patients. (6)

M. pneumoniae infection occurs throughout the year but can cause periodic outbreaks within small communities. Transmission is by person-to-person contact, and infection spreads slowly, most often within closed populations (e.g., households, schools, businesses).

M. pneumoniae is the pathogen most often associated with atypical pneumonia. Onset is insidious, over several days to a week. Constitutional symptoms, which usually are present, include headache exacerbated by a cough, malaise,myalgias, and sore throat. The cough is usually dry, paroxysmal, and worse at night.

The clinical course of pneumonia caused by M. pneumoniae is usually mild and self-limited. The mortality rate is approximately 1.4 percent. (2) However, pulmonary complications can be significant and include effusion, empyema, pneumothorax, and respiratory distress syndrome.

M. pneumoniae infection may be associated with several extrapulmonary manifestations. Skin manifestations include erythema multiforme, erythema nodosum, maculopapular and vesicular eruptions, and urticaria. Neurologic derangements include aseptic meningitis, cerebral ataxia, encephalitis, Guillain-Barre syndrome, and transverse myelitis. The production of cold agglutinins can result in hemolytic anemia, especially when M. pneumoniae titers are high. Finally, complications such as myocarditis, pancreatitis, pericarditis, and polyarthritis can occur.

CHLAMYDIA PNEUMONIAE

Chlamydia pneumoniae is an obligate intracellular organism capable of persistent latent infection. Humans are the only known reservoir. Transmission results from contact with respiratory secretions, with an incubation period of several weeks.

By the age of 20 years, one half of persons in the United States have detectable levels of antibody to C. pneumoniae. (7) The antibody is present in 75 percent of elderly persons.7 C. pneumoniae infection is more likely to occur in older patients with comorbid diseases than in those who are otherwise healthy. (8)

Patients with C. pneumoniae infection often present with sore throat, headache, and a cough that can persist for months if treatment is not initiated early. (9) Sputum is usually scant or nonexistent, and a low-grade fever is usually present. Chest radiographs tend to show less extensive infiltrates than are seen with other causes of pneumonia, although significant infiltrates have been reported. (10)

Most cases of C. pneumoniae infection are mild, but severe disease can occur, necessitating admission to an intensive care unit. The mortality rate has been estimated to be 9 percent, and death usually is associated with secondary infection and underlying comorbid disease. (2)

LEGIONELLA PNEUMOPHILA

Like C. pneumoniae, Legionella species are intracellular organisms. Legionella pneumophila is the most pathogenic species, and several serotypes have been identified. Serotype 1 has been associated with most reported human cases of pneumonia caused by L. pneumonphila. (11)

Infection occurs from exposure to legionellae organisms in the environment. Person-to-person spread has not been reported. Legionellae are found most commonly in freshwater and man-made water systems. The pathogens also can be found in moist soil, especially near streams and ponds. Man-made systems for heating and cooling water can be prime environments for the proliferation of legionellae, because of conditions such as temperatures between 32[degrees]C (89.6[degrees]F) and 45[degrees]C (113[degrees]F), stagnation of water, and the presence of scale sediment and amebas. (12) Condensers, cooling towers, respiratory therapy equipment, showers, water faucets, and whirlpools have been associated with outbreaks of legionellosis. (13)

Risk factors for the development of legionellosis include overnight stays outside the home, recent home plumbing work, renal or liver failure, diabetes, malignancy, and other conditions that compromise the immune system. (14) Legionnaires' disease may present with a wide spectrum of symptoms ranging from mild cough and low-grade fever to high fever, altered mental status, and respiratory failure. (15) Nonspecific symptoms may occur early in the disease and include headache, muscle aches, anorexia, and malaise. (15) Diarrhea and other gastrointestinal symptoms are present in 20 to 40 percent of cases. (15) Leukocytosis is a common laboratory finding, and the sputum Gram stain often shows an abundance of inflammatory cells without a predominance of organisms. (11)

Among cases of CAP with atypical causes, legionnaires' disease has the most severe clinical course, and illness can become progressively more severe if the infection is not treated appropriately and early. Although extrapulmonary manifestations are rare, legionellosis has been implicated in cases of myocarditis, pericarditis, and prosthetic valve endocarditis, as well as glomerulonephritis, pancreatitis, and peritonitis. (15) When CAP is caused by Legionella species, the mortality rate is 14 percent. (2)

Therapy

Therapy for pneumonia is empiric because specific pathogens usually are not identified at the time treatment is initiated. Several classes of antibiotics are effective against atypical pathogens. However, because C. pneumoniae and Legionella species are intracellular organisms and M. pneumoniae lacks a cell wall, beta-lactams are not effective.

Erythromycin and, in some cases, tetracycline have been traditional choices for the treatment of pneumonia caused by atypical pathogens. There are few (if any) clinical trials demonstrating the efficacy of erythromycin for Legionella infection. However, erythromycin and tetracycline are effective against M. pneumoniae and have been shown to reduce symptom duration in C. pneumoniae infection. (5,8)

Newer macrolides such as azithromycin (Zithromax) and clarithromycin (Biaxin) have good activity against M. pneumoniae, C. pneumoniae, and Legionella species, and generally are better tolerated than erythromycin. (16-20) Doxycycline (Vibramycin) also is effective, (21) typically is associated with fewer gastrointestinal side effects, and is a less expensive alternative.

Fluoroquinolones have demonstrated excellent activity against M. pneumoniae, C. pneumoniae, and Legionella species. In addition, fluoroquinolones have the advantage of once-daily dosing and excellent bioavailability, whether they are given intravenously or orally. (22-25)

The Infectious Diseases Society of America (IDSA) (26) has published a comprehensive, evidence-based guideline to the management of CAP in adults who are immunocompetent. Empiric treatment recommendations are based on whether patients are treated as outpatients or inpatients (Table 2). (26) The decision to hospitalize can be guided by the mortality prediction rule shown in Figure 1. (27)

Blood cultures do not have to be performed before outpatient therapy is started. However, the IDSA (26) recommends performing blood cultures in hospitalized patients, if possible before antibiotics are administered. Sputum Gram stain and culture also are recommended in these patients. Antibiotic therapy should be initiated within four hours of hospitalization. (28)

Treatment Challenges

FAILURE OF OUTPATIENT MANAGEMENT

Patients treated with antibiotics may fail outpatient management for a number of reasons, such as antibiotic resistance, poor compliance with or intolerance of oral antibiotics, obstructing lesions (e.g., foreign body, cancer), empyema, and incorrect diagnosis. (26) Table 3 (26,29) lists alternate diagnoses that may mimic CAP.

PARAPNEUMONIC EFFUSION AND EMPYEMA

Up to 57 percent of patients with CAP have pleural effusions on chest radiographs. (30) Empyema, defined as pus in the pleural space, should be drained by chest tube, image-guided catheter, thoracoscopy, or thoracotomy. (26) Even if the pleural fluid does not contain free-flowing frank pus, it should be drained when the pH level is less than 7.2 or the Gram stain is positive. (26) Some experts recommend drainage for any parapneumonic effusion that measures more than 10 mm on a lateral decubitus radiograph. (30)

CHILDREN

An evidence-based guideline on the management of CAP in children, developed by a children's hospital, is available online. (31) Pneumonia should be suspected in a child who presents with fever and tachypnea. Because infection with an atypical pathogen is unlikely in children two months to five years of age, the recommended treatment in these patients is high-dose amoxicillin (80 to 90 mg per kg daily) for seven to 10 days. A cephalosporin or macrolide is recommended in those who are allergic to penicillin. Macrolides are recommended for the treatment of CAP in children older than five years, because of the increased likelihood of infection with M. pneumoniae or C. pneumoniae in older children. Macrolides also provide coverage for S. pneumoniae.

Hospitalization should be considered for any child with CAP and is necessary if a child requires oxygen or intravenous therapy, or if treatment compliance or follow-up may be an issue. Treatment with a macrolide plus a betalactam (high-dose amoxicillin or parenteral ceftriaxone [Rocephin]) should be considered in children with more severe pneumonia. Children treated as outpatients should have a follow-up examination within 24 to 72 hours. (31)

ELDERLY PATIENTS

Elderly patients with CAP may present with few respiratory signs or symptoms of pneumonia. Instead, they may have altered mental status or a history of falls. (32) Elderly patients also are more likely to have significant comorbid conditions, such as chronic obstructive pulmonary disease, congestive heart failure, or renal disease, and are particularly susceptible to silent aspiration. (32,33) Aspiration pneumonia should be suspected in patients with a condition that compromises consciousness or swallowing, especially when the chest radiograph shows infiltrates in dependent segments of the lung. Antibiotics effective against anaerobic organisms from the mouth should be given (Table 2). (26)

Pneumonia acquired in a nursing home has a high rate of morbidity and mortality (up to 44 percent). (34) It is the leading infectious illness requiring transfer from a nursing home to a hospital. (32) Guidelines on when to hospitalize are provided in Table 4.34 Recommended treatment regimens for patients in nursing homes are summarized in Table 5. (32)

IMMUNOCOMPROMISED PATIENTS

The guidelines and recommendations given throughout this article are intended for immunocompetent patients. Immunocompromised patients may develop pneumonia from organisms such as Pneumocystis carinii, Candida species, and Aspergillus species, as well as other opportunistic organisms not reviewed in this article.

Prevention Strategies

Despite evidence showing that pneumococcal vaccine significantly reduces the occurrence of pneumococcal pneumonia in persons who are immunocompetent, immunization rates are modest at best. (35) Vaccination is more likely when it is recommended by a patient's physician or by someone in the physician's office. (35) Although influenza is not reviewed in this article, it is an important contributor to CAP; therefore, patients at risk for CAP should be given annual influenza vaccination. (26) In addition, long-term oral hygiene appears to reduce the incidence of pneumonia among elderly persons living in nursing homes. (36)

BIOTERRORISM AGENTS THAT MAY CAUSE PNEUMONIA

Several organisms that can be used in biological weapons may cause illness that presents as CAP (Table 6). (26,37) It is important for physicians to be aware of potential bioterrorist tactics and risks, and the resulting health care demands. Information on bioterrorism response is available on the American Academy of Family Physicians Web site (http://www.aafp.org/btresponse.xml).

SUDDEN ACUTE RESPIRATORY SYNDROME

Periodically, an epidemiologic investigation prompted by an outbreak of pneumonia leads to the identification of a previously unrecognized organism. (26) Sudden acute respiratory syndrome (SARS) is an example. SARS, which is thought to have originated in a Hong Kong apartment building, is caused by a coronavirus (SARS-CoV). During the SARS outbreak of 2002 to 2003, over 8,000 probable cases were reported from 29 different countries. Twenty-nine cases were reported in the United States. (38)

SARS presents with a prodrome of symptoms of a flu-like illness (fever, chills, myalgias, headache, diarrhea), followed in two to seven days by cough, dyspnea and, possibly, acute respiratory distress syndrome. (26,38) The case-fatality rate for SARS is about 9.6 percent. (38) No deaths in the United States have been linked to SARS. (38) Information about SARS and travel guidelines are available at the Centers for Disease Control and Prevention Web site (http://www.cdc.gov/ncidod/sars/).

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(5.) Liu C. Mycoplasma pneumonia. In: Hoeprich PD, Jordan MC, Ronald AR, eds. Infectious diseases: a treatise of infectious processes. 5th ed. Philadelphia: Lippincott, 1994:411-16.

(6.) Marston BJ, Plouffe JF, File TM Jr, Hackman BA, Salstrom SJ, Lipman HB, et al. Incidence of community-acquired pneumonia requiring hospitalization. Results of a population-based active surveillance study in Ohio. The Community-Based Pneumonia Incidence Study Group. Arch Intern Med 1997;157:1709-18.

(7.) Kuo CC, Jackson LA, Campbell LA, Grayston JT. Chlamydia pneumoniae (TWAR). Clin Microbiol Rev 1995;8:451-61.

(8.) Kauppinen M, Saikku P. Pneumonia due to Chlamydia pneumoniae: prevalence, clinical features, diagnosis, and treatment. Clin Infect Dis 1995;21(suppl 3):S244-52.

(9.) Wright SW, Edwards KM, Decker MD, Grayston JT, Wang S. Prevalence of positive serology for acute Chlamydia pneumoniae infection in emergency department patients with persistent cough. Acad Emerg Med 1997;4:179-83.

(10.) McConnell CT Jr, Plouffe JF, File TM, Mueller CF, Wong KH, Skelton SK, et al. Radiographic appearance of Chlamydia pneumoniae (TWAR strain) respiratory infections. CBPIS Study Group. Community-based Pneumonia Incidence Study. Radiology 1994;192:819-24.

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(12.) Shands KN, Ho JL, Meyer RD, Gorman GW, Edelstein PH, Mallison GF, et al. Potable water as a source of Legionnaires' disease. JAMA 1985;253:1412-6.

(13.) Butler JC, Fields BS, Breiman RF. Prevention and control of Legionellosis. Infect Dis Clin Pract 1997;6/7:458-64.

(14.) Straus WL, Plouffe JF, File TM Jr, Lipman HB, Hackman BH, Salstrom SJ, et al. Risk factors for domestic acquisition of legionnaires disease. Ohio Legionnaires Disease Group. Arch Intern Med 1996;156:1685-92.

(15.) Stout JE, Yu VL. Legionellosis. N Engl J Med 1997;337:682-7.

(16.) Cassell GH, Drnec J, Waites KB, Pate MS, Duffy LB, Watson HL, et al. Efficacy of clarithromycin against Mycoplasma pneumoniae. J Antimicrob Chemother 1991;27(suppl A):47-59.

(17.) Fernandes PB, Bailer R, Swanson R, Hanson CW, McDonald E, Ramer N, et al. In vitro and in vivo evaluation of A-56268 (TE-031), a new macrolide. Antimicrob Agents Chemother 1986;30:865-73.

(18.) Kuo CC, Jackson LA, Lee A, Grayston JT. In vitro activities of azithromycin, clarithromycin, and other antibiotics against Chlamydia pneumoniae. Antimicrob Agents Chemother 1996;40:2669-70.

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Members of various family practice departments develop articles for "Practical Therapeutics." This article is one in a series coordinated by the Department of Family Medicine at Naval Hospital Jacksonville, Jacksonville, Fla. Guest editor of the series is Anthony J. Viera, LCDR, MC, USNR.

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Navy Medical Corps or the U.S. Navy at large.

KRISTOPHER P. THIBODEAU, LCDR, MC, USN, and ANTHONY J. VIERA, LCDR, MC, USNR Naval Hospital Jacksonville, Jacksonville, Florida

KRISTOPHER P. THIBODEAU, LCDR, MC, USN, is staff family physician at Naval Hospital Sigonella, Italy. He received his medical degree from the Uniformed Services University of the Health Sciences F. Edward Hebert School of Medicine, Bethesda, Md., and completed a residency in family medicine at Naval Hospital Jacksonville, Jacksonville, Fla. ANTHONY J. VIERA, LCDR, MC, USNR, is a staff family physician at Naval Hospital Jacksonville and assistant professor of family medicine at the Uniformed Services University of the Health Sciences F. Edward Hebert School of Medicine. He received his medical degree from the Medical University of South Carolina College of Medicine, Charleston, and completed a residency in family medicine at Naval Hospital Jacksonville.

Address correspondence to LCDR Kristopher P. Thibodeau, MC, USN, Naval Hospital Sigonella, PSC 836, Box 0036, FPO AE 09636-0036 (e-mail:kthibodeau@sig.med.navy.mil). Reprints are not available from the authors.

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