Ambulatory management of lower respiratory tract infections
James S. Tan
Bronchitis and pneumonia account for millions of office visits and antibiotic prescriptions each year. Antibiotics generally are ineffective in acute bronchitis, which is most frequently viral in origin. Since acute bronchial infection in association with chronic lung disease may be caused by antimicrobial-susceptible organisms, antibiotics may be useful in treating acute exacerbations of chronic bronchitis. [1,2] Pneumonia is often caused by antimicrobial-susceptible organisms, and timely antibiotic therapy can reduce complications and mortality. 
The choice of antimicrobial therapy for a bacterial lower respiratory tract infection is relatively straightforward when the etiologic agent and its antibiotic susceptibility are known. However, whether in the office or in the hospital setting, the clinical presentation is usually not specific enough to make a firm etiologic diagnosis.  Therefore, the initial choice of antibiotic is often based on a knowledge of local epidemiology, the most likely microbial agents and their antibiotic susceptibility.
In the past two decades, antibiotic selection has become more complicated because of bacterial resistance to established antibiotic regimens, the recognition of new respiratory pathogens and the occurrence of iatrogenic infections. Recently, penicillin-resistant strains of Streptococcus pneumoniae and ampicillin-resistant strains of Haemophilus influenzae have been isolated more frequently in the United States. [5,6] Infectious agents such as Legionella species,  a new human strain of Chlamydia pneumoniae (TWAR strain)  and Moraxella catarrhails [9,10] have been recognized as respiratory pathogens. In addition, microbial agents that were considered non-pathogenic have been found to cause infection in immunosuppressed patients.
Most patients with community-acquired pneumonia are initially seen by primary care physicians. The majority of these patients have mild symptoms, and only about 7 percent require hospitalization. The mortality rate for hospitalized patients is as high as 5 to 10 percent. 
Diagnosis of Lower Respiratory Tract Infection
When a patient with a lower respiratory infection is seen in the office or the hospital, the choice of antimicrobial therapy should be based not only on clinical and laboratory findings but also on historical information, such as local epidemiology, recent travel by the patient, exposure to animals and exposure to individuals who may be sick.
Most of the clinical manifestations of the various pneumonias overlap.  Tew and associates  demonstrated that chest radiography is not helpful for differentiating bacterial from nonbacterial pneumonia. Therefore, microbiologic means should be used to identify the causative agent in pneumonia.
Identification of the causative agent and knowledge of its antimicrobial susceptibility are important in determining the approach to treatment. Consequently, Gram stain and culture of lower respiratory secretions should be performed.
Due to contamination with saliva, culture of expectorated sputum has been presumed to be less desirable than culture of sputum obtained with an invasive procedure. However, a good sputum specimen can be distinguished from a contaminated one by careful examination of a sputum smear.  An acceptable gram-stained specimen should have less than 10 squamous epithelial cells per low-power field. Spubum culture reports should be interpreted together with the gram-stained result. Microbiology laboratories have attempted to improve the value of the culture report by eliminating poorly collected sputum samples that do not fulfill the criteria of Murray and Washington. 
Numerous investigators have demonstrated the lack of specificity of sputum cultures in the diagnosis of pneumonia. [14,15] However, invasive techniques for obtaining sputum are rarely indicated in ambulatory patients and are infrequently required for hospitalized patients.
For most patients with community-acquired pneumonia, empiric therapy can be started when it is established that an appropriate specimen is not available for evaluation. Blood cultures, when positive, provide a definitive diagnosis and, in spite of a relatively low yield, should be obtained routinely in patients hospitalized for pneumonia. [16,17]
Immunologic and Direct Antigen Detection Tests
AND STREPTOCOCCUS PNEUMONIAE
Immunologic diagnosis of community-acquired pneumonia in adults can be attempted using methods that detect bacterial antigen in tissue fluids and microorganism-specific antibody (IgM or IgG) in serum.  Detection of H. influenzae and S. pneumoniae antigens has been evaluated using counter-immunoelectrophoresis, latex agglutination, coagglutination and enzyme immunoassay. 
Recent studies suggest that testing for pneumococcal antigen in sputum and other body fluids has not replaced the Gram stain as a rapid diagnostic test. [19,20] Although results show that H. influenzae antigen testing in serum and urine is sensitive and specific, wide acceptance of this test for diagnosing pneumonia in adults has not occurred. 
Legionella pneumophila infection can be diagnosed using direct fluorescent antibody (DFA) staining of the organism, or antigen detection by DNA probe in respiratory secretions. [7,21] Soluble L. pneumophila antigens in urine, detected by radioimmunoassay, enzyme immunoassay and latex agglutination, can also help diagnose legionnaire’s disease.  Legionella-specific serum IgM or IgG antibody is less useful for rapid diagnosis, but it can confirm cases that were negative on culture or direct antigen detection tests. [20,21,23] The acute serum specimen can be frozen for subsequent testing if a convalescent specimen is collected. Routine testing of the acute specimen alone, even with IgM- and IgG-specific reagents, usually is not helpful.
Urine L. pneumophila antigen tests are potentially useful, since their sensitivity is approximately 80 percent. Commercially marketed reagents are now available, but require clinical evaluation before they can be recommended. A reasonable approach would be to order culture and serology only when L. pneumophila infection is considered. Culture results usually are available three to five days after sputum sampling.
DFA or DNA probe testing of respiratory secretions should be reserved for populations in which the prevalence of disease exceeds 5 percent and the volume of tests performed allows batch testing. DFA is also appropriate for tissue obtained by biopsy.
Mycoplasma pneumoniae is difficult to culture. When cultures do grow this organism, they do not become positive for one to three weeks.  Alternative diagnostic tests include the detection of cold agglutinins and the identification of M. pneumoniae RNA sequences with a DNA probe. [22,24,25] Although the cold agglutinin test lacks sensitivity and specificity, it is useful because of its wide availability.
Tests for Mycoplasma IgG antibody require paired acute and convalescent sera to document a fourfold rise in antibody titer. Tests for Mycoplasma-specific IgM can be performed on a single acute specimen; the detection of any amount of IgM suggests a recent or acute infection. [22,25] To avoid misleading results, IgM should first be separated and the test performed on the purified fraction.
Use of a DNA probe to diagnose M. pneumoniae infection is limited by a lack of clinical evaluations supporting the acceptability of commercially available reagents. The potential value of this proble, however, is significant.
A practical approach would be to request a cold agglutinin test and a Mycoplasma-specific IgM test. A positive result with either or both tests would suggest infection. A negative test would necessitate a convalescent serum specimen three to five weeks later to look for a significant rise in IgG titer. 
CHLAMYDIA PNEUMONIAE (TWAR)
Culture of C. pneumoniae is generally not available. Diagnostic C. pneumoniae antigen tests also are not available. However, tests for antibody detection of C. pneumoniae using microimmunofluorescence and complement fixation are available commercially. The IgM antibody response may take up to three weeks to appear. The IgG antibody takes over six to eight weeks to be detectable during the primary infection. The IgG antibody level rises rapidly during reinfection. When only one sample is available, an IgM titer greater than 16 or an IgG titer greater than 512 provides presumptive evidence of acute infection. 
Community-Acquired Bacterial Pneumonia
S. pneumoniae and M. pneumoniae are the most common pathogens in community-acquired pneumonia. [3,4,17] H. influenzae and M. catarrhalis are frequently found in patients with underlying pulmonary problems. L. pneumophila infections may be associated with localized outbreaks. More recently, C. pneumoniae has been found in patients with upper respiratory tract infections, bronchitis and pneumonia. The manifestations of both classic and atypical pneumonias frequently are nonspecific. 
Resistance of infectious agents to antibiotics has complicated treatment of community-acquired lower respiratory tract infections. Strains of penicillin-resistant pneumococci have been isolated in many hospitals in the United States. This resistance is the result of alteration of penicillin-binding protein and is not mediated by beta-lactamase production. These pneumococci are also resistant to cephalosporins. Therefore, intravenous vancomycin (Vancocin) is the drug of choice. 
Beta-lactamase production is the most commonly encountered mode of ampicillin resistance in H. influenzae and M. catarrhalis infections. Trimethoprimsulfamethoxazole (Bactrim, Septra), the tetracyclines, the cephalosporins, beta-lactamase inhibitor-penicillin derivatives and the fluoroquinolones should be adequate to treat these infections.
The goal of empiric therapy is to choose a regimen that will be effective agains the most likely pathogen. When rapid diagnostic techniques are not available, therapy should be started based on a knowledge of the susceptibility pattern of the common respiratory pathogens in the community. A reasonable attempt should be made to obtain a Gram stain of respiratory secretions before antimicrobial therapy is started. 
With the aid of the Gram stain results, the physician can initiate treatment based on a suspected pathogen. When gram-positive cocci in chains or pairs are found as the predominant organism, S. pneumoniae is the most likely causative organism. When the smear indicates gram-positive cocci in clusters, staphylococcal infection must be considered. The finding of gram-negative coccobacilli in the smear is compatible with H. influenzae. Gram-negative diplococci suggest M. catarrhalis, and gram-negative rods are indicative of Enterobacteriaceae, Pseudomonas and anaerobic organisms. When mixed gram-positive and gram-negative organisms are seen, aspiration of oral flora should be suspected.
Penicillin is the drug of choice for patients with pneumococcal pneumonia, which can be suspected when the Gram stain shows numerous leukocytes and a predominance of gram-positive diplococci. For patients who are allergic to penicillin, trimethoprim-sulfamethoxazole, erythromycin, clindamycin (Cleocin) or a cephalosporin, such as cefuroxime axetil (Ceftin) or cefaclor (Ceclor), may be used. Ciprofloxacin (Cipro) has not been shown to be consistently effective. Ofloxacin (Floxin) appears to have better activity,  but like ciprofloxacin, it is not a first-line agent (Table 1).[TABULAR DATA OMITTED]
The incidence of ampicillin resistance in adult H. influenzae infections in adults ranges from 10 to 30 percent and varies from center to center. [5,6,31] Ampicillin resistance is most frequently associated with beta-lactamase production. Combination therapy with a penicillin derivative, a beta-lactamase inhibitor (e.g., amoxicillin-clavulanate potassium [Augmentin], ticarcillin-clavulanate potassium [Timentin], ampicillin-sulbactam sodium [Unasyn]) and some cephalosporins (e.g., cefuroxime, cefaclor) is quite effective against this group of organisms.
M. catarrhalis, formerly known as Neisseria or Branhamella catarrhalis, was considered a respiratory tract commensal until 1971, when it was recognized that the organism might be a cause of respiratory infection. [6,10] Because approximately 85 percent of M. catarrhalis strains produce beta-lactamase,  ampicillin therapy generally is not effective. Patients with M. catarrhalis infection may be treated with the same antimicrobial agents listed for beta-lactamase-producing H. influenzae strains. Erythromycin is also effective.
M. pneumoniae is a common respiratory pathogen that infects the upper and lower respiratory tract. The organism is frequently unrecognized because it is rarely associated with serious complications and death.  Erythromycin and tetracy are the drugs primarily used in the treatment of Mycoplasma infection. Patients treated with either agent improve clinically, but the culture remains positive.
L. pneumophila is a less common cause of lower respiratory tract infection than S. pneumoniae and M. pneumoniae. However, isolated cases of legionnaire’s disease have occurred with enough frequency to warrant concern. L. pneumophila infection also occurs in immunocompromised patients. The organism is susceptible to erythromycin, trimethoprimsulfamethoxazole, doxycycline (Vibramycin) and the fluoroquinolones. Erythromycin is the recommended first-line agent. In more serious infections, rifampin (Rifadin), 600 mg every 12 hours, should be added. 
C. pneumoniae (TWAR strain) respiratory infection is generally a mild disease. Fang and colleagues  observed a mortality rate of 4.5 percent for this disease, with most of the deaths occurring in the elderly. Erythromycin is effective in treating C. pneumoniae respiratory infections.
While most patients with lower respiratory tract infection may be treated as outpatients, elderly or immunosuppressed patients may require hospitalization. Patients with lung infection involving multiple lobes, impending respiratory compromise or extrapulmonary complications are also candidates for hospitalization.
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JAMES S. TAN, M.D. is professor of internal medicine and chairman of the infectious disease section at Northeastern Ohio Universities College of Medicine, Rootstown. Dr. Tan also serves as chairman of the Department of Medicine at Akron (Ohio) City Hospital.
THOMAS M. FILE, JR., M.D. is professor of internal medicine at Northeastern Ohio Universities College of Medicine and chief of the infectious disease service at Akron City Hospital.
RICHARD B. THOMSON, JR., PH.D. is associate professor of microbiology and immunology at Northeastern Ohio Universities College of Medicine and director of the clinical microbiology laboratory at Akron City Hospital.
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