Community-Acquired Pneumonia: Work-up and Management
Author: Thomas M. File, MD, FACP, FCCP, Professor of Internal Medicine, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio; Chief Infectious Disease Service, Summa Health System, Akron, Ohio.
Peer Reviewers: M. W. Craig, MD, Senior Vice President, Medical Affairs, Miami Valley Hospital, Dayton, Ohio; and Carol A. Kemper, MD, Clinical Associate Professor of Medicine, Stanford University, Santa Clara Valley Medical Center.
Editor’s Note—Community-acquired pneumonia (CAP) is a common disorder that is potentially life-threatening, especially in older adults and those with comorbid disease. Several changes have occurred during this past decade that have affected the management of CAP including: the identification of new pathogens (i.e., Chlamydia pneumoniae and Sin nombre [Hantavirus]), increasing resistance of standard pathogens (most notably Streptococcus pneumoniae), new methods of diagnosis (i.e., Legionella urinary antigen, PCR), and new antimicrobial agents (i.e., new macrolides and fluoroquinolones).1,2 Despite substantial progress in therapeutic options, CAP remains a primary cause of death in the United States from infectious disease and there continues to be major controversies in the clinical management of these infections. This review discusses the incidence, pathogenesis, etiology, as well as the diagnostic studies and antimicrobial management of these important infections.
Effect and Incidence
In the United States, approximately 4 million cases of pneumonia occur each year, accounting for 10 million physician visits, approximately 500,000 hospitalizations, and approximately 45,000 deaths.1 While the mortality has ranged from 2% to 30% among hospitalized patients, the average rate is approximately 14%.1 Mortality is estimated to be less than 1% for patients who are not hospitalized. The total estimated cost of treating CAP is $23 billion, with indirect costs (e.g., absence from work) accounting for a large percent of this total.3
For persons between the ages of 5-60 years, various studies have reported the incidence of CAP between 100-500 per 100,000 population.3 CAP occurs more commonly in children younger than the age of 5 years and in adults older than the age of 65 years. In 1987, Houston and colleagues retrospectively evaluated the incidence of pneumonia (nursing home and community-associated) in elderly residents (> 65 years of age) in Homestead County, Minneapolis, MN.4 The overall incidence rate for an initial episode of pneumonia was 3032 per 100,000 population; this rate rose to 7923 per 100,000 among residents aged 85 or older. In a prospective study of all adult patients (> 18 years of age) hospitalized for CAP in two counties in Ohio during 1991 (Ohio Community-Based Pneumonia Incidence Study), Marston and associates reported an incidence rate of 280 cases per 100,000 population.5 The incidence of CAP is highest in the winter months.
Pathogenesis
In a healthy individual, the lower respiratory tract is kept essentially sterile by effective pulmonary defense mechanisms that include anatomic barriers as well as humoral, cell-mediated, and phagocytic immunity. Although normal individuals commonly aspirate their upper respiratory tract flora, pneumonia develops when there is a breakdown in pulmonary host defenses, when the invading organisms are virulent, or when a large inoculum size of the microorganism is introduced.6,7 Oropharyngeal aspiration remains the most common route of acquiring pneumonia. Less commonly, the organisms enter the lungs by inhalation or by a hematogenous or contiguous route.
The elderly appear at increased risks for the development of pneumonia related to a variety of factors, such as increased number of underlying diseases, increased hospitalization, age-related impairments and impairment of host defense mechanisms, and decreased immune response. When recurrent episodes of bacterial pneumonia occur, the presence of underlying predisposition (i.e., congenital defects of the immune system, immunoglobulin [Ig] deficiency, HIV infection) should be considered.
Certain pathogens cause pneumonia more commonly among persons with specific risk factors. For example, pneumococcal pneumonia is classically a disease of the elderly or those with a variety of medical conditions that include chronic heart disease, chronic obstructive pulmonary disease (COPD), asplenia, immunoglobulin deficiency, hematological malignancy, and HIV infection. S. pneumoniae is second only to Pneumocystis carinii as the most common identifiable cause of acute pneumonia in patients with AIDS.8 Legionella is an opportunist and is less common among healthy children and young adults. It is an important cause of CAP in organ transplant recipients and in patients with renal failure, and it occurs with increased frequency in smokers and in patients with COPD. Risk factors for sporadic Legionella in otherwise healthy adults include recent travel with an overnight stay outside the home and recent repair of domestic plumbing.9 While it has historically been believed that Mycoplasma pneumoniae primarily involves children and young adults, recent evidence suggests that this organism causes CAP among adults of any age.5
Etiology
The etiologic pathogens of CAP have changed in prevalence over time.10,11 While S. pneumoniae remains the most common causative pathogen, a number of newer pathogens, such as C. pneumoniae and Sin nombre virus (Hantavirus), have been recognized in recent years. (See Table 1.) Based on a review of more than 15 published reports from North America that covers more than two decades and from mostly hospitalized patients, the ranges for prevalence of specific bacterial pathogens as causes of pneumonia are reported as: S. pneumoniae, 20-60%; Haemophilus influenzae, 3-10%; M. pneumoniae, 1-6%; C. pneumoniae, 4-6%; Legionella spp., 2-8%; viruses, 2-13%; aspiration, 6-10%; Staphylococcus aureus, 3-5%; gram-negative bacilli, 3-10%; and miscellaneous, 10-20% (P. carinii was excluded from most of these reports but may account for up to 15% of CAP cases from some urban areas, reflecting the prevalence of HIV in these communities; in addition, few of these studies used techniques to isolate anaerobic bacteria, which have been identified in studies using transtracheal aspirates and may account for 20-30% of all cases of CAP).2
| Table 1. Pathogens Associated With Community-Acquired Pneumonia | |
Traditional pathogens |
Less common pathogens in immunocompetent host |
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An awareness of the epidemiological considerations is important for the appropriate formulation of management guidelines related to such patients. Table 2 lists the most common pathogens associated with CAP based on the collective results of recent studies and based on severity of illness as judged by site of care (outpatient vs inpatient).12 Despite the awareness of newly recognized pathogens and the greater number of possible pathogens associated with CAP, S. pneumoniae remains the most common causative agent and it is clearly the most common cause of fatal CAP.13 Geographic and epidemiological associations influence likely causes of CAP (which may, in part, explain differences in prevalence rates of studies from different locations). Pathogens with geographic association include Legionella spp., Sin nombre virus, endemic fungi, Coxiella burnetii, Francisella tularensis, and tuberculosis.
| Table 2. Etiology of Community-Acquired Pneumonia | ||
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| Ambulatory Patients
S. pneumoniae M. pneumoniae H. influenzae C. pneumonaie "Viruses" |
Hospitalized (non-ICU)
S. pneumoniae M. pneumoniae C. pneumoniae H. influenzae Legionella spp. Aspiration |
Severe (ICU)
S. pneumoniae H. influenzae Legionella spp. Gram-negative bacilli S. aureus |
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*Based on collective data from recent studies Excluding Pneumocystis spp. Adapted from: File TM, Jr. Etiology and incidence of community-acquired pneumonia. Infect Dis Clin Pract 1996;5(Suppl 4): S123-S135.
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Multiple Organisms/Mixed Infections. Although objective confirmation is often difficult, multiple organisms that infect a patient concurrently or sequentially may cause cases of CAP. For example, influenza A or C. pneumoniae infection might be followed by a secondary infection with S. pneumoniae. The incidence of mixed infection varies among different studies and, to a certain extent, depends upon the classification (i.e., definite vs presumed) of the diagnosis. In three well-defined studies of patients requiring hospitalization, the incidence ranged from 2.7% to 10%.5,14,15 The most common combination of causative agents was S. pneumoniae and another pathogen (often detected by serologic means). The clinical importance of multiple organisms/mixed infections has not been clearly established; however, identification of one pathogen should not preclude evaluation for other diagnostic etiologies when CAP is not responding to therapy.
Unknown Pathogens. Recent studies show that the number of cases in which an etiologic agent cannot be identified in hospitalized patients continues to be approximately 50%. This problem persists despite the use of a wide range of tests including blood cultures, chest radiographs, sputum gram stain, and cultures, serology for specific pathogens, antigen detection methods, and evasive techniques (e.g., fiberoptic bronchoscopy). Even when appropriate testing is combined with a careful analysis of regional and institutional specific patterns of infection, it is often not possible to identify the etiologic agent. Some of these cases may reflect the effective prior antibiotic therapy (which may have prevented identification of an etiologic agent by standard microbiologic methods) or the inability to pinpoint a specific agent may be infection caused by organisms for which specific testing was not routinely performed (i.e., Histoplasma capsulatum, C. burnetii, or anaerobes or respiratory viruses). Additionally, some of these cases may in fact have a noninfectious etiology. Other cases likely result from, as yet, undefined pathogens. Given the emergence over the last two decades of newly recognized pathogens, it is most likely that additional pathogens will be identified. Noninfectious diseases whose symptoms may mimic those of CAP include pulmonary emboli, congestive heart failure, bronchogenic carcinoma, pulmonary lymphoma, pulmonary fibrosis, rheumatologic diseases, Wegner’s granulomatosis, sarcoidosis, and bronchiolitis obliterans-organizing pneumonia (BOOP).
Antimicrobial Resistance
The emergence of multidrug-resistant strains of S. pneumoniae and other respiratory pathogens has become a significant problem in the United States as well as other countries worldwide. Recent multicenter studies of S. pneumoniae isolates obtained in the United States indicate that penicillin-nonsusceptible rates are approximately 30-40%, with high-level resistance rates approximating 10-20% (minimum inhibitory concentrations of ³ 2 mcg/mL).16-19 Resistance to other commonly used agents (cephalosporins, macrolides, doxycycline, trimethoprim/sulfamethoxazole) is increasing as well. S. pneumoniae isolates that are multidrug-resistant are uniformly susceptible to vancomycin and almost all (~ 99%) are susceptible to the new fluoroquinolone agents (levofloxacin, sparfloxacin, grepafloxacin, trovafloxacin). While the clinical relevance of in vitro resistance concerning outcome for CAP is controversial, it is known that in vitro resistance with regard to high-level resistant pneumococcus for infections such as meningitis and otitis media is significant (i.e., associated with clinical failure).19,20 Furthermore, recent studies are beginning to show that CAP due to S. pneumoniae with high-level resistance have higher rates of clinical failure.21 It is anticipated that as rates of high-level resistance continue to increase, antimicrobial resistance will be a more significant problem in the future.
Diagnostic Considerations
The importance of appropriate diagnostic evaluation of patients with symptoms suggestive of pneumonia is important for several reasons that include: the accurate diagnosis of CAP; appropriate assessment of severity of illness; appropriate use of microbiologic studies to establish the etiologic diagnosis.
Accurate Diagnosis of CAP. Adult patients who are immunocompetent should be evaluated for pneumonia if they present with symptoms that include cough, sputum production, labored breathing (including altered breath sounds and rales), and/or fever. These symptoms may also be present in patients with upper respiratory infections, other lower respiratory tract infections (i.e., acute bronchitis, chronic bronchitis) as well as noninfectious diseases (i.e., reactive airways disease, atelectasis, CHF, vasculitis, pulmonary embolism, and malignancy). An accurate diagnosis of the presence of CAP is crucial since antibiotic therapy is usually indicated for pneumonia but is usually not indicated for most upper respiratory infections or acute bronchitis since most are viral in etiology. Given the potential danger associated with antibiotic overuse (increased bacteria resistance and unnecessary side effects) and the cost of inappropriate therapy, recent guidelines recommend that a chest x-ray be obtained for the routine evaluation of patients with suspected CAP.1 The rationale is to appropriately establish the diagnosis of pneumonia and differentiate from other respiratory illnesses such as acute bronchitis.
While it is generally considered that the chest x-ray is necessary to establish a diagnosis of CAP, I acknowledge that in the "real world," many healthcare providers treat patients on the basis of clinical manifestations only. It is important to point out, however, that distinguishing CAP from other respiratory illnesses such as acute bronchitis is extremely difficult on clinical grounds alone. A review of published studies of pneumonia indicate that no combination of clinical findings can reliably define the presence of pneumonia,22 but the absence of any vital sign abnormality or any abnormalities on chest auscultation substantially reduces the likelihood of pneumonia. Since pneumonia is, therefore, unlikely in the absence of these abnormalities, I recommend a strategy of assigning a diagnosis of CAP without chest x-ray confirmation be considered only if there are significant clinical manifestations (i.e., new cough with abnormal vital signs and localized auscultatory findings). To treat with antibiotics in the absence of these findings is likely to be associated with the use of these agents for nonbacterial respiratory illnesses (i.e., viral or noninfectious) and contribute to the already high risk of antimicrobial resistance.
Determining Severity of Illness/Appropriate Site of Care. A key decision facing the clinician is whether to hospitalize the patient with CAP. A general consensus is that approximately 75% of patients can be appropriately treated as outpatients.1 A recently published prediction rule on pneumonia, Patient Outcomes Research Team (PORT) can assist clinicians in making the decision.23 The pneumonia PORT prediction rule has been validated as a method for identifying patients at risk for death and other complications requiring hospitalization. Additionally, Fine and associates suggest that it can be used as a method for triaging patients as to site of care. This is because those patients who are below risk mortality probably do not require hospitalization, while those at high risk should be treated and monitored in a hospital setting. The prediction rule stratifies patients to one of five categories by using a point system based on several variables. Most of the information needed for scoring is easily available from the history and physical examination. The prediction rule is a two-step process and first considers age (> 50 years), the presence of comorbid conditions, and the presence of abnormal vital signs. If any of these are present, then points are assigned to each condition for which a total score and classification can be determined. (See Figure 1 and Table 3.)
| Table 3. Risk-Class Mortality Rates for Patients with Pneumonia | ||||
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Adapted from: Fine MJ, et al. A prediction rule to identifylow-risk patients with community-acquired pneumonia. N Engl J Med 1997;336:243-250. _______________________________________________________________________________________ |
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Etiologic Diagnosis. The use of diagnostic studies to determine the etiologic agents of CAP is controversial. It is recognized that there must be a balance between reasonable diagnostic procedures and empirical therapy. Published guidelines for management of CAP differ somewhat on the emphasis of performing microbiologic studies (i.e., gram stain and culture of expectorated sputum) in an attempt to establish the etiologic diagnosis of CAP. Recommendation from guidelines published in 1993 by the American Thoracic Society primarily advocate empiric therapy without a great emphasis on diagnostic studies for etiology.24 More recent guidelines published by the Infectious Diseases Society of America (IDSA) place more emphasis on attempting to establish the etiologic diagnosis by microbiologic means because of the increasing antibiotic resistance and the concern for overuse of antibiotics.1 Although no studies have clearly demonstrated a cost-effective advantage of establishing an etiologic diagnosis, there have been no specific studies designed to address this issue. An obvious concern regarding empiric therapy without pathogen identification is the possible overuse of certain agents, which could lead to more resistance. Theoretically, one could be able to lessen the emergence of resistance and, therefore, focus on therapy if one could identify the pathogen. The rationale for establishing an etiologic diagnosis for patients with CAP include:
• To permit optimal antibiotic selection in terms of activity against a specific pathogen (this especially applies to drug-resistant S. pneumoniae [DRSP]);
• To permit antibiotic selection that limits the consequences of antibiotic abuse in terms of cost, resistance, and adverse drug effects;
• To identify pathogens of potential epidemiological significance such as Legionella, Hantavirus, and DRSP.
A detailed history can be important in the evaluation of CAP and may be helpful in making an etiologic diagnosis. Epidemiological clues that may lead to diagnosis considerations are listed in Table 4.
| Table 4. Epidemiological and Underlying Conditions Related to Specific Pathogens in Selected Patients with CAP | |
| Condition | Commonly Encountered Pathogens |
| Alcoholism | S. pneumoniae, anaerobes, gram-negative bacilli |
| COPD/smoker | S. pneumoniae, H. influenzae, M. catarrhalis, Legionella spp. |
| Nursing-home residency | S. pneumoniae, gram-negative bacilli, H. influenzae, S. aureus, anaerobes, C. pneumoniae |
| Poor dental hygiene | anaerobes |
| Epidemic Legionnaire’s disease | Legionella spp. |
| Exposure to bats or soil enriched with bird droppings | Histoplasma capsulatum |
| Exposure to birds | C. psittaci |
| Exposure to rabbits | Francisella tularensis |
| HIV infection (early stage) | S. pneumoniae, H. influenzae, M. tuberculosis |
| Travel to the southwestern United States | Coccidioides immitis |
| Exposure to farm animals or parturient cats | Coxiella burnetii* |
| Influenza active in community | Influenza, S. pneumoniae, S. aureus, Streptococcus pyogenes, H. influenzae |
| Suspected large-volume aspiration | anaerobes, chemical pneumonitis |
| Structural disease of the lung (bronchiectasis or cystic fibrosis) | Pseudomonas aeruginosa, Burkholderia (Pseudomonas) cepacia, or S. aureus |
| Injection drug use | S. aureus, anaerobes, M. tuberculosis |
| Airway obstruction | anaerobes |
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*Agent of Q fever. Reprinted with permission from The University of Chicago Press. Bartlett JG, et al. Community-acquired pneumonia in adults: Guidelines for management. Clin Infect Dis 1998;26:811-838.
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Once the clinical diagnosis of CAP has been made, consideration should be directed toward the microbiological diagnosis. Table 5 reviews the diagnostic studies recommended in the recently published guidelines of the IDSA.1 For patients who are not seriously ill and do not require hospitalization, it is desirable, but optional, to perform a sputum gram stain with or without culture. A complete blood count with differential is sometimes useful for further assessing the illness in terms of severity, the presence of associated conditions, or chronicity. Additional studies are recommended for patients who require hospitalization. (See Table 5.) Many pathogens require specialized tests for detection (e.g., Legionella, Mycobacteria, viruses) for which the local microbiology laboratory should be consulted. The routine rapid diagnostic test is gram staining of respiratory secretions (usually expectorated sputum); other tests include the direct fluorescent antibody (DFA) stain of sputum or the urinary antigen assay for Legionella, and the acid-fast stain for detection of mycobacterial infections. The urine antigen assay for L. pneumophila serogroup 1 is a test that is technically nondemanding and can reliably and rapidly detect up to 70% of cases of Legionnaires’ disease.1 Many rapid diagnostic tests such as PCR assays are early in development, not commonly available, or not sufficiently accurate. Diagnostic procedures that provide identification of a specific etiology within 24-72 hours can still be useful for guiding continued therapy. Serological tests are usually not available in the initial evaluation of patients with CAP, but they may provide data that are useful for epidemiological surveillance. Ideally, however, an acute-phase serum specimen can be obtained from patients and stored. If the etiology of a case remains in question, a convalescent-phase serum specimen can be obtained, and paired serological studies can be performed.
| Table 5. Diagnostic Studies for Evaluation of CAP |
Baseline assessment
Reprinted with permission from The University of Chicago Press. Bartlett JG, et al. Community-acquired pneumonia in adults: Guidelines for management. Clin Infect Dis 1998;26:811-838.
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Of all the potential diagnostic studies, the most controversial is the study of expectorated sputum—specifically, the significance and predictability of the gram stain. It is acknowledged that this test is limited by the fact that many patients cannot produce a good specimen, patients often receive antimicrobial agents prior to evaluation, and many specimens show inconclusive results. Nonetheless, the sputum gram stain can provide useful information to guide diagnosis and early therapy when there is a predominance of a particular organism from appropriate specimen. Although many reports indicate that the yield of pathogens in expectorated sputum from patients with CAP is only 30-40%, this yield may often be increased with improved techniques; furthermore, a negative specimen may enhance the probability of an atypical agent (which may influence the antimicrobial treatment decision), and a good-quality specimen that does not show or yield S. aureus or gram-negative bacilli provides good evidence that these organisms are not present.1 This information may prove useful for patients who do not respond to treatment, since conventional cultures of posttreatment specimens are relatively useless. The validity of the gram stain is related directly to the experience of the interpreter. Indeed, some discrepant findings concerning the sputum gram stain presumably are explained by the quality of specimens and technical expertise. Ideally, a nurse or physician should obtain a deep cough expectorated sputum sample before antibiotics are administered. Antimicrobial therapy should be initiated promptly and should not be delayed in an attempt to obtain pretreatment specimens from acutely ill patients for microbiologic studies [it is my experience that if patients are able to produce a good sputum sample, they are able to readily expectorate such specimens . If patients are unable to produce expectorated sputum in an expeditious manner, appropriate empirical antimicrobial therapy should be initiated without delay].
Induced sputum samples have established value for the detection of P. carinii and M. tuberculosis, and, usually, such samples should be generally limited to cases with these diagnostic considerations.1 Bronchoscopy and quantitative cultures and other invasive diagnostic techniques should be reserved for selected clinical settings or clinical studies. Examples of clinical settings that may justify the use of bronchoscopy include pneumonia in immunocompromised hosts, suspected tuberculosis in the absence of productive cough, selected cases of chronic pneumonia, pneumonia associated with suspected neoplasm or foreign body, suspected P. carinii pneumonia, some cases in which intubation is required, and suspected conditions that require lung biopsy.
Therapeutic Considerations
Antimicrobials are the mainstay of treatment for most patients with CAP. Decisions concerning antimicrobial therapy are guided by several considerations such as spectrum of activity, pharmacokinetics, efficacy, safety profile, cost, and whether a specific pathogen is identified (i.e., empiric vs pathogen-directed therapy). Recommendations for antimicrobial therapy in this review represent those included in the guidelines of the IDSA.1 (See Table 6.)
| Table 6. Empirical Antibiotic Selection for Patients with CAP |
Outpatients
Generally preferred: Macrolides,* fluoroquinolones, or doxycycline |
Modifying factors
Suspected penicillin-resistant S. pneumoniae: fluoroquinolones Suspected aspiration: amoxicillin/clavulanate Young adult (> 17-40 y): doxycycline |
Hospitalized patients General medical ward
Generally preferred: B-lactam with or without a macrolide* or a fluoroquinolone(alone) |
Modifying factors
Structural disease of the lung: antipseudomonal penicillin, a carbapenem, or cefepime plus a macrolide* or a fluoroquinolone plus an aminoglycoside |
| * Azithromycin, clarithromycin, or erythromycin.
Levofloxacin, sparfloxacin, grepafloxacin, trovafloxacin, or another fluoroquinolone with enhanced activity against S. pneumoniae. Cefotaxime, ceftriaxone, or a B-lactam-B-lactamase inhibitor. § Ampicillin/sulbactam, or ticarcillin/clavulanate, or piperacillin/tazobactam (for structural disease of the lung, ticarcillin/clavulanate or piperacillin). Reprinted with permission from The University of Chicago Press. Bartlett JG, et al. Community-acquired pneumonia in adults: Guidelines for management. Clin Infect Dis 1998;26:811-838.
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Pathogen-Directed Therapy. Treatment options are obviously simplified if the etiologic agent is established or strongly suspected. The guidelines advocate pathogen-directed therapy whenever possible. Keep in mind that diagnostic procedures that provide identification of a specific etiology within 24-72 hours can still be useful for guiding continued therapy. If, for example, an appropriate culture reveals the isolation of S. pneumoniae, therapy can be based on its susceptibility. If that isolate is determined to be susceptible to penicillin, the IDSA guidelines recommend the use of that agent.1 By selecting a narrow spectrum agent such as penicillin (or amoxicillin orally), hopefully the selective pressure for resistance is reduced. This information is often available at the time for consideration if switched from parenteral to oral therapy and may be used to direct specific antimicrobial choices.
Empirical Therapy. Although the IDSA guidelines stress the importance of attempting to define the etiologic agents when possible so that directed-therapy can be implemented, it is acknowledged that the majority of patients will be empirically treated. This is particularly the case for outpatients in whom little diagnostic testing is emphasized.
The selection of specific antimicrobial regimens is based largely on the most likely pathogens (see Table 2), clinical experience, and in vitro activity. Other important considerations in antibiotic selection concern patient tolerance, ease of administration, severity of illness, patient age, clinical features, comorbidity, exposures, epidemiological setting, and prevalence of drug-resistance among respiratory tract pathogens.
Antimicrobial agents generally considered effective for the most common (key) respiratory pathogens (i.e., S. pneumoniae, H. influenzae, M. pneumoniae, C. pneumoniae, L. pneumophila) include the macrolides, newer fluoroquinolones, and doxycycline. While the beta-lactam antibiotics (such as penicillins and cephalosporins) are effective against most isolates of S. pneumoniae and H. influenzae, they are not clinically effective for the "atypical pathogens." Penicillins combined with beta-lactamase inhibitors (amoxicillin/clavulante, ticarcillin/clavulanate, ampilicillin/sulbactam, and piperacillin/ tazobactam) are active against beta-lactamase-producing organisms including H. influenzae, anaerobes, M. catarrhalis, and methicillin-susceptible strains of S. aureus. These drugs offer no advantage over penicillin G for the treatment of high-level resistant S. pneumoniae strains because the mechanism for resistance is alteration of penicillin-binding proteins, not beta-lactamase production. The cephalosporins, which are most active against strains of S. pneumoniae, are cefotaxime and ceftriaxone (parenterally) and cefpodoxime, cefuroxime and cefprozil (orally). The carbapenem agents, imipenem and meropenem, have reasonable activity against S. pneumoniae including most strains that are intermediately resistant to penicillin.
Regarding the macrolides, the newer agents (clarithromycin and azithromycin) are better tolerated than erythromycin. All three are effective in the treatment of CAP caused by M. pneumoniae, C. pneumoniae, and Legionella species. Approximately 10-20% of S. pneumoniae isolates are resistant to macro-lides in vitro; this rate is substantially higher among penicillin-resistant strains.16 Although to date there has been little evidence of clinical failure of such infections treated with the macrolides, caution is necessary when these agents are used empirically in suspected cases of pneumococcal pneumonia. Erythromycin is relatively inactive against H. influenzae. Clarithromycin also has relatively limited in vitro activity against some strains of H. influenzae; however, its 14-OH metabolite is more active than the parent drug, which improves its effectiveness. Of the three macrolides, azithromycin is most active in vitro against Legionella, H. influenzae, and M. pneumoniae, whereas clarithromycin is the most active against S. pneumoniae and C. pneumoniae.
Regarding the fluoroquinolones, ciprofloxacin has only marginal activity against S. pneumoniae, and there are anecdotal reports of clinical failures with this drug in the treatment of pneumococcal pneumonia. The newer fluoroquinolones (levofloxacin, sparfloxacin, grepafloxacin, trovafloxacin) have enhanced activity against S. pneumoniae (including drug-resistant strains) and initial studies have shown good results.25,26 These newer agents are all highly active against H. influenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, and Legionella. Although resistance of S. pneumoniae is presently not significant, there is concern that excessive and inappropriate use of these drugs may lead to resistant strains. From the standpoint of doxycycline, this agent is active in vitro against the atypical pathogens including M. pneumoniae, C. pneumoniae, and Legionella. In the past, S. pneumoniae and H. influenzae have been quite susceptible; there is concern about occasional resistance, including resistance in S. pneumoniae in 5-10% of isolates.1
Outpatients. The preferred antimicrobials listed in the IDSA guidelines include (in no special order) a macrolide, a fluoroquinolone with enhanced activity against S. pneumoniae, or doxycycline. (See Table 6.) Of the macrolides, clarithromycin or azithromycin are preferred if H. influenzae is suspected. Alternative options include amoxicillin/clavulanate and some second-generation cephalosporins (i.e., those with better activity against S. pneumoniae, which include cefuroxime, cefpodoxime, or cefprozil). As indicated in the guidelines, however, these beta-lactam agents will not be active against atypical pathogens; therefore, they should probably be reserved for patients with higher likelihood of S. pneumoniae or H. influenzae (i.e., older patients and/or smokers).
It was the intent of the IDSA panel to recommend options of therapy for which the healthcare provider can choose based on factors listed earlier. Therefore none of the preferred options are listed as "first line" or "second line." However, the panel does list as a modifying factor the concern for drug-resistant S. pneumoniae—for which a fluoroquinolone with enhanced activity against S. pneumoniae is recommended. Since known risk factors for DRSP in adults include recent use of antimicrobials and immunosuppression, the newer fluoroquinolones may be appropriate "first-line" agents in this setting. Otherwise, the macrolides with the caveat that increasing resistance to the macrolides is concerning are preferred. Doxycycline is appropriate for young adults (< 50) without significant underlying conditions and amoxicillin/clavulanate for "aspiration" pneumonia because of its good activity against oral anaerobes.
Patients Requiring Hospital Admission. For patients requiring hospital admission, recommendations are given for patients being treated on a general ward vs. those requiring admission to the ICU. For those treated on a general ward, preferred options include either a beta-lactam with or without a macrolide or a new fluoroquinolone. (See Table 6.) Alternative choices are also given in Table 6. Since the publication of the guidelines, new data suggest that the outcome of hospitalized patients with CAP will be improved if a macrolide is routinely added to a beta-lactam agent for empiric therapy. Therefore, a macrolide should always be included if the beta-lactam containing option is chosen for empiric therapy.
For those who require treatment in an ICU, aggressive therapy should be instituted immediately using either a parenteral macrolide (erythromycin or azithromycin) or a parenteral fluoroquinolone plus a third-generation cephalosporin, or a beta-lactam/beta-lactamase inhibitor. Modifying factors for patients requiring hospitalization include recommendations for patients with structural disease of the lung (i.e., bronchiectasis to include effective therapy for Pseudomonas as well as S. pneumoniae), for penicillin allergy, and for suspected aspiration.
Length and Route of Antimicrobial Treatment. There is a lack of controlled trials that can specifically address the question as to length of therapy. The decision is usually based on the pathogen isolated, response to treatment, comorbid illness, and complications. Until further data are forthcoming, it seems reasonable to treat bacterial infections such as those caused by S. pneumoniae until a patient is afebrile for 72 hours.1 Pneumonia caused by M. pneumoniae or C. pneumoniae should probably be treated for at least two weeks, as should Legionnaires’ disease in immunocompetent individuals. Azithromycin may be used for shorter courses of treatment because of its longer half-life in tissue.
For many pathogens, there is no clear advantage of intravenous therapy over oral therapy if oral bioavailability and activity are adequate and the panel endorses use of oral antimicrobial agents for patients who tolerate these drugs. However, for most patients admitted to the hospital, the common practice is to at least begin therapy with intravenous drugs. Changing from intravenous to oral therapy is associated with a number of economic, healthcare, and social benefits. Conditions for changing from intravenous to oral include stable or improving condition, ability to ingest drugs, and a functional gastrointestinal tract. In most cases, these conditions are met within 2-3 days. Ideally, the parenteral drugs should be given in an oral formulation with adequate bioavailability; if no oral formulation is available, an oral agent with a similar spectrum of activity should be selected on the basis of in vitro or predicted susceptibility patterns of established or probable pathogen(s).
Prevention
The importance of prevention of CAP is addressed by current CDC guidelines for the use of influenza and pneumococcal vaccines. More than half of patients hospitalized with pneumococcal disease has been hospitalized in the previous five years. Consequently, unvaccinated patients with risk factors for pneumococcal disease and influenza should be vaccinated during hospitalization whenever possible. There is no contraindication for use of either vaccine immediately after an episode of pneumonia such as before discharge from the hospital. The vaccines are cost-effective and can be given simultaneously.
References
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4. Houston MS, et al. Community-acquired lower respiratory tract infection in the elderly: A community-based study of incidence and outcome. J Am Board Fam Pract 1995;8(5):347-356.
5. Marston BJ, et al, and the CBPIS Study Group. Incidence of community-acquired pneumonia requiring hospitalization: Results of a population-based active surveillance study in Ohio. Arch Intern Med 1997.
6. Nelson S, et al. Pathophysiology of pneumonia. Clin Chest Med 1995;16(1):1-12.
7. Reynolds HY. Respiratory infections: Community-acquired pneumonia and newer microbes. Lung 1996;174:207-224.
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