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      Prevalence of gram negative bacteria causing community acquired pneumonia among adults in Mwanza City, Tanzania

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          Abstract

          Background

          Community acquired pneumonia (CAP) in adults is still a common and serious illness in the sub-Saharan Africa. Identification of the pathogens is crucial in the management of CAP. This study was done to determine the common bacterial pathogens, treatment outcomes and associated factors for microbiological confirmed CAP among adults attending the Bugando Medical Centre and Sekou Toure hospital in the city of Mwanza, Tanzania.

          Methods

          This was a hospital based cross sectional study involving patients with community acquired pneumonia attending Bugando Medical Centre and Sekou Toure regional Hospital. Demographic and other data were collected using standardized data collection tool. Sputum culture was done followed by identification of the isolates and antibiotics susceptibility testing.

          Results

          A total of 353 patients were enrolled in the study. Out of 353 sputum samples, 265(75%) were of good quality. Of 353 non-repetitive sputum cultures, 72/353 (20.4, 95% CI: 16.2–24.6) were positive for the bacterial pathogens with five patients having more than one pathogen. Good quality sputa had significantly higher yield of pathogenic bacteria than poor quality sputa (26.1% vs.3.4%, P = 0.001). The majority 64 (83.1%) of the isolates were gram negative bacteria. Common bacteria isolated were Klebsiella pneumoniae 23/77(29.9%), Streptococcus pyogenes 10/77 (13.0%), Pseudomonas aeruginosa 9/77 (11.7%) and Escherichia coli 7/77 (9.1%). Of 23  K. pneumoniae isolates, 20/23 (87.0%) were resistant to ceftriaxone. Resistance to ceftriaxone was found to be associated with prolongation of CAP symptoms ( p = 0.009).

          Conclusion

          Gram negative bacteria resistant to ampicillin, amoxicillin/clavulanic acid and ceftriaxone were most frequently isolated bacteria among adults’ patients with CAP attending BMC and Sekou Toure hospital. Routine sputum culture should be performed to guide appropriate treatment of CAP among adults in developing countries.

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          Most cited references 35

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          Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults

          Executive Summary Improving the care of adult patients with community-acquired pneumonia (CAP) has been the focus of many different organizations, and several have developed guidelines for management of CAP. Two of the most widely referenced are those of the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS). In response to confusion regarding differences between their respective guidelines, the IDSA and the ATS convened a joint committee to develop a unified CAP guideline document. The guidelines are intended primarily for use by emergency medicine physicians, hospitalists, and primary care practitioners; however, the extensive literature evaluation suggests that they are also an appropriate starting point for consultation by specialists. Substantial overlap exists among the patients whom these guidelines address and those discussed in the recently published guidelines for health care-associated pneumonia (HCAP). Pneumonia in nonambulatory residents of nursing homes and other long-term care facilities epidemiologically mirrors hospital-acquired pneumonia and should be treated according to the HCAP guidelines. However, certain other patients whose conditions are included in the designation of HCAP are better served by management in accordance with CAP guidelines with concern for specific pathogens. Implementation of Guideline Recommendations. 1. Locally adapted guidelines should be implemented to improve process of care variables and relevant clinical outcomes. (Strong recommendation; level I evidence.) Enthusiasm for developing these guidelines derives, in large part, from evidence that previous CAP guidelines have led to improvement in clinically relevant outcomes. Consistently beneficial effects in clinically relevant parameters (listed in table 3) followed the introduction of a comprehensive protocol (including a combination of components from table 2) that increased compliance with published guidelines. The first recommendation, therefore, is that CAP management guidelines be locally adapted and implemented. Documented benefits. 2. CAP guidelines should address a comprehensive set of elements in the process of care rather than a single element in isolation. (Strong recommendation; level III evidence.) 3. Development of local CAP guidelines should be directed toward improvement in specific and clinically relevant outcomes. (Moderate recommendation; level III evidence.) Site-of-Care Decisions Almost all of the major decisions regarding management of CAP, including diagnostic and treatment issues, revolve around the initial assessment of severity. Site-of-care decisions (e.g., hospital vs. outpatient, intensive care unit [ICU] vs. general ward) are important areas for improvement in CAP management. Hospital admission decision 4. Severity-of-illness scores, such as the CURB-65 criteria (confusion, uremia, respiratory rate, low blood pressure, age 65 years or greater), or prognostic models, such as the Pneumonia Severity Index (PSI), can be used to identify patients with CAP who may be candidates for outpatient treatment. (Strong recommendation; level I evidence.) 5. Objective criteria or scores should always be supplemented with physician determination of subjective factors, including the ability to safely and reliably take oral medication and the availability of outpatient support resources. (Strong recommendation; level II evidence.) 6. For patients with CURB-65 scores ⩾2, more-intensive treatment—that is, hospitalization or, where appropriate and available, intensive in-home health care services—is usually warranted. (Moderate recommendation; level III evidence.) Physicians often admit patients to the hospital who could be well managed as outpatients and who would generally prefer to be treated as outpatients. Objective scores, such as the CURB-65 score or the PSI, can assist in identifying patients who may be appropriate for outpatient care, but the use of such scores must be tempered by the physician's determination of additional critical factors, including the ability to safely and reliably take oral medication and the availability of outpatient support resources. ICU admission decision. 7. Direct admission to an ICU is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring intubation and mechanical ventilation. (Strong recommendation; level II evidence.) 8. Direct admission to an ICU or high-level monitoring unit is recommended for patients with 3 of the minor criteria for severe CAP listed in table 4. (Moderate recommendation; level II evidence.) In some studies, a significant percentage of patients with CAP are transferred to the ICU in the first 24–48 h after hospitalization. Mortality and morbidity among these patients appears to be greater than those among patients admitted directly to the ICU. Conversely, ICU resources are often overstretched in many institutions, and the admission of patients with CAP who would not directly benefit from ICU care is also problematic. Unfortunately, none of the published criteria for severe CAP adequately distinguishes these patients from those for whom ICU admission is necessary. In the present set of guidelines, a new set of criteria has been developed on the basis of data on individual risks, although the previous ATS criteria format is retained. In addition to the 2 major criteria (need for mechanical ventilation and septic shock), an expanded set of minor criteria (respiratory rate, >30 breaths/min; arterial oxygen pressure/fraction of inspired oxygen (PaO2/FiO2) ratio, 20 mg/dL; leukopenia resulting from infection; thrombocytopenia; hypothermia; or hypotension requiring aggressive fluid resuscitation) is proposed (table 4). The presence of at least 3 of these criteria suggests the need for ICU care but will require prospective validation. Diagnostic Testing 9. In addition to a constellation of suggestive clinical features, a demonstrable infiltrate by chest radiograph or other imaging technique, with or without supporting microbiological data, is required for the diagnosis of pneumonia. (Moderate recommendation; level III evidence.) Recommended diagnostic tests for etiology 10. Patients with CAP should be investigated for specific pathogens that would significantly alter standard (empirical) management decisions, when the presence of such pathogens is suspected on the basis of clinical and epidemiologic clues. (Strong recommendation; level II evidence.) Recommendations for diagnostic testing remain controversial. The overall low yield and infrequent positive impact on clinical care argue against the routine use of common tests, such as blood and sputum cultures. Conversely, these cultures may have a major impact on the care of an individual patient and are important for epidemiologic reasons, including the antibiotic susceptibility patterns used to develop treatment guidelines. A list of clinical indications for more extensive diagnostic testing (table 5) was, therefore, developed, primarily on the basis of 2 criteria: (1) when the result is likely to change individual antibiotic management and (2) when the test is likely to have the highest yield. 11. Routine diagnostic tests to identify an etiologic diagnosis are optional for outpatients with CAP. (Moderate recommendation; level III evidence.) 12. Pretreatment blood samples for culture and an expectorated sputum sample for stain and culture (in patients with a productive cough) should be obtained from hospitalized patients with the clinical indications listed in table 5 but are optional for patients without these conditions. (Moderate recommendation; level I evidence.) 13. Pretreatment Gram stain and culture of expectorated sputum should be performed only if a good-quality specimen can be obtained and quality performance measures for collection, transport, and processing of samples can be met. (Moderate recommendation; level II evidence.) 14. Patients with severe CAP, as defined above, should at least have blood samples drawn for culture, urinary antigen tests for Legionella pneumophila and Streptococcus pneumoniae performed, and expectorated sputum samples collected for culture. For intubated patients, an endotracheal aspirate sample should be obtained. (Moderate recommendation; level II evidence.) The most clear-cut indication for extensive diagnostic testing is in the critically ill CAP patient. Such patients should at least have blood drawn for culture and an endotracheal aspirate obtained if they are intubated; consideration should be given to more extensive testing, including urinary antigen tests for L. pneumophila and S. pneumoniae and Gram stain and culture of expectorated sputum in nonintubated patients. For inpatients without the clinical indications listed in table 5, diagnostic testing is optional (but should not be considered wrong). Antibiotic Treatment Empirical antimicrobial therapy.Empirical antibiotic recommendations (table 7) have not changed significantly from those in previous guidelines. Increasing evidence has strengthened the recommendation for combination empirical therapy for severe CAP. Only 1 recently released antibiotic has been added to the recommendations: ertapenem, as an acceptable β-lactam alternative for hospitalized patients with risk factors for infection with gram-negative pathogens other than Pseudomonas aeruginosa. At present, the committee is awaiting further evaluation of the safety of telithromycin by the US Food and Drug Administration before making its final recommendation regarding this drug. Recommendations are generally for a class of antibiotics rather than for a specific drug, unless outcome data clearly favor one drug. Because overall efficacy remains good for many classes of agents, the more potent drugs are given preference because of their benefit in decreasing the risk of selection for antibiotic resistance. Outpatient treatment 15. Previously healthy and no risk factors for drug-resistant S. pneumoniae (DRSP) infection: A macrolide (azithromycin, clarithromycin, or erythromycin) (strong recommendation; level I evidence) Doxycycline (weak recommendation; level III evidence) 16. Presence of comorbidities, such as chronic heart, lung, liver, or renal disease; diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressing conditions or use of immunosuppressing drugs; use of antimicrobials within the previous 3 months (in which case an alternative from a different class should be selected); or other risks for DRSP infection: A. A respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg]) (strong recommendation; level I evidence) B. A. β-lactam plus a macrolide (strong recommendation; level I evidence) (High-dose amoxicillin [e.g., 1 g 3 times daily] or amoxicillin-clavulanate [2 g 2 times daily] is preferred; alternatives include ceftriaxone, cefpodoxime, and cefuroxime [500 mg 2 times daily]; doxycycline [level II evidence] is an alternative to the macrolide.) 17. In regions with a high rate (>25%) of infection with high-level (MIC, ⩾16 µg/mL) macrolide-resistant S. pneumoniae, consider the use of alternative agents listed above in recommendation 16 for any patient, including those without comorbidities. (Moderate recommendation; level III evidence.) Inpatient, non-ICU treatment 18. A respiratory fluoroquinolone (strong recommendation; level I evidence) 19. β-lactam plus a macrolide (strong recommendation; level I evidence) (Preferred β-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients; with doxycycline [level III evidence] as an alternative to the macrolide. A respiratory fluoroquinolone should be used for penicillin-allergic patients.) Increasing resistance rates have suggested that empirical therapy with a macrolide alone can be used only for the treatment of carefully selected hospitalized patients with nonsevere disease and without risk factors for infection with drug-resistant pathogens. However, such monotherapy cannot be routinely recommended. Inpatient, ICU treatment 20. β-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin (level II evidence) or a fluoroquinolone (level I evidence) (strong recommendation) (For penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended.) 21. For Pseudomonas infection, use an antipneumococcal, antipseudomonal β-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin (750-mg dose) or the above β-lactam plus an aminoglycoside and azithromycin or the above β-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone (for penicillin-allergic patients, substitute aztreonam for the above β-lactam). (Moderate recommendation; level III evidence.) 22. For community-acquired methicillin-resistant Staphylococcus aureus infection, add vancomycin or linezolid. (Moderate recommendation; level III evidence.) Infections with the overwhelming majority of CAP pathogens will be adequately treated by use of the recommended empirical regimens. The emergence of methicillin-resistant S. aureus as a CAP pathogen and the small but significant incidence of CAP due to P. aeruginosa are the exceptions. These pathogens occur in specific epidemiologic patterns and/or with certain clinical presentations, for which empirical antibiotic coverage may be warranted. However, diagnostic tests are likely to be of high yield for these pathogens, allowing early discontinuation of empirical treatment if results are negative. The risk factors are included in the table 5 recommendations for indications for increased diagnostic testing.Pathogens suspected on the basis of epidemiologic considerations. Risk factors for other uncommon etiologies of CAP are listed in table 8, and recommendations for treatment are included in table 9. Pathogen-directed therapy. 23. Once the etiology of CAP has been identified on the basis of reliable microbiological methods, antimicrobial therapy should be directed at that pathogen. (Moderate recommendation; level III evidence.) 24. Early treatment (within 48 h of the onset of symptoms) with oseltamivir or zanamivir is recommended for influenza A. (Strong recommendation; level I evidence.) 25. Use of oseltamivir and zanamivir is not recommended for patients with uncomplicated influenza with symptoms for >48 h (level I evidence), but these drugs may be used to reduce viral shedding in hospitalized patients or for influenza pneumonia. (Moderate recommendation; level III evidence.) Pandemic influenza 26. Patients with an illness compatible with influenza and with known exposure to poultry in areas with previous H5N1 infection should be tested for H5N1 infection. (Moderate recommendation; level III evidence.) 27. In patients with suspected H5N1 infection, droplet precautions and careful routine infection control measures should be used until an H5N1 infection is ruled out. (Moderate recommendation; level III evidence.) 28. Patients with suspected H5N1 infection should be treated with oseltamivir (level II evidence) and antibacterial agents targeting S. pneumoniae and S. aureus, the most common causes of secondary bacterial pneumonia in patients with influenza (level III evidence). (Moderate recommendation.) Time to first antibiotic dose. 29. For patients admitted through the emergency department (ED), the first antibiotic dose should be administered while still in the ED. (Moderate recommendation; level III evidence.) Rather than designating a specific window in which to initiate treatment, the committee felt that hospitalized patients with CAP should receive the first antibiotic dose in the ED. Switch from intravenous to oral therapy. 30. Patients should be switched from intravenous to oral therapy when they are hemodynamically stable and improving clinically, are able to ingest medications, and have a normally functioning gastrointestinal tract. (Strong recommendation; level II evidence.) 31. Patients should be discharged as soon as they are clinically stable, have no other active medical problems, and have a safe environment for continued care. Inpatient observation while receiving oral therapy is not necessary. (Moderate recommendation; level II evidence.) Duration of antibiotic therapy. 32. Patients with CAP should be treated for a minimum of 5 days (level I evidence), should be afebrile for 48–72 h, and should have no more than 1 CAP-associated sign of clinical instability (table 10) before discontinuation of therapy (level II evidence). (Moderate recommendation.) 33. A longer duration of therapy may be needed if initial therapy was not active against the identified pathogen or if it was complicated by extrapulmonary infection, such as meningitis or endocarditis. (Weak recommendation; level III evidence.) Other Treatment Considerations 34. Patients with CAP who have persistent septic shock despite adequate fluid resuscitation should be considered for treatment with drotrecogin alfa activated within 24 h of admission. (Weak recommendation; level II evidence.) 35. Hypotensive, fluid-resuscitated patients with severe CAP should be screened for occult adrenal insufficiency. (Moderate recommendation; level II evidence.) 36. Patients with hypoxemia or respiratory distress should receive a cautious trial of noninvasive ventilation unless they require immediate intubation because of severe hypoxemia (PaO2/FiO2 ratio, 30 days) high-dose corticosteroid treatment; and patients with congenital or acquired immunodeficiency or those infected with HIV who have CD4 cell counts 1700 emergency department (ED) visits in 19 hospitals randomized between pathway and “conventional” management found that admission rates among low-risk patients at pathway hospitals decreased (from 49% to 31% of patients in Pneumonia Severity Index [PSI] classes I–III; P 1.5 days [20, 21]. Markers of process of care can also change with the use of a protocol. The time to first antibiotic dose has been effectively decreased with CAP protocols [22, 27, 29]. A randomized, parallel group study introduced a pneumonia guideline in 20 of 36 small Oklahoma hospitals [29], with the identical protocol implemented in the remaining hospitals in a second phase. Serial measurement of key process measures showed significant improvement in time to first antibiotic dose and other variables, first in the initial 20 hospitals and later in the remaining 16 hospitals. Implementing a guideline in the ED halved the time to initial antibiotic dose [22]. 2. CAP guidelines should address a comprehensive set of elements in the process of care rather than a single element in isolation. (Strong recommendation; level III evidence.) Common to all of the studies documented above, a comprehensive protocol was developed and implemented, rather than one addressing a single aspect of CAP care. No study has documented that simply changing 1 metric, such as time to first antibiotic dose, is associated with a decrease in mortality. Elements important in CAP guidelines are listed in table 2. Of these, rapid and appropriate empirical antibiotic therapy is consistently associated with improved outcome. We have also included elements of good care for general medical inpatients, such as early mobilization [30] and prophylaxis against thromboembolic disease [31]. Although local guidelines need not include all elements, a logical constellation of elements should be addressed. 3. Development of local CAP guidelines should be directed toward improvement in specific and clinically relevant outcomes. (Moderate recommendation; level III evidence.) In instituting CAP protocol guidelines, the outcomes most relevant to the individual center or medical system should be addressed first. Unless a desire to change clinically relevant outcomes exists, adherence to guidelines will be low, and institutional resources committed to implement the guideline are likely to be insufficient. Guidelines for the treatment of pneumonia must use approaches that differ from current practice and must be successfully implemented before process of care and outcomes can change. For example, Rhew et al. [32] designed a guideline to decrease LOS that was unlikely to change care, because the recommended median LOS was longer than the existing LOS for CAP at the study hospitals. The difficulty in implementing guidelines and changing physician behavior has also been documented [28, 33]. Clinically relevant outcome parameters should be evaluated to measure the effect of the local guideline. Outcome parameters that can be used to measure the effect of implementation of a CAP guideline within an organization are listed in table 3. Just as it is important not to focus on one aspect of care, studying more than one outcome is also important. Improvements in one area may be offset by worsening in a related area; for example, decreasing admission of low-acuity patients might increase the number of return visits to the ED or hospital readmissions [25]. Site-of-Care Decisions Almost all of the major decisions regarding management of CAP, including diagnostic and treatment issues, revolve around the initial assessment of severity. We have, therefore, organized the guidelines to address this issue first.Hospital admission decision.The initial management decision after diagnosis is to determine the site of care—outpatient, hospitalization in a medical ward, or admission to an ICU. The decision to admit the patient is the most costly issue in the management of CAP, because the cost of inpatient care for pneumonia is up to 25 times greater than that of outpatient care [34] and consumes the majority of the estimated $8.4–$10 billion spent yearly on treatment. Other reasons for avoiding unnecessary admissions are that patients at low risk for death who are treated in the outpatient setting are able to resume normal activity sooner than those who are hospitalized, and 80% are reported to prefer outpatient therapy [26, 35]. Hospitalization also increases the risk of thromboembolic events and superinfection by more-virulent or resistant hospital bacteria [36]. 4. Severity-of-illness scores, such as the CURB-65 criteria (confusion, uremia, respiratory rate, low blood pressure, age 65 years or greater), or prognostic models, such as the PSI, can be used to identify patients with CAP who may be candidates for outpatient treatment. (Strong recommendation; level I evidence.) Significant variation in admission rates among hospitals and among individual physicians is well documented. Physicians often overestimate severity and hospitalize a significant number of patients at low risk for death [20, 37, 38]. Because of these issues, interest in objective site-of-care criteria has led to attempts by a number of groups to develop such criteria [39–48]. The relative merits and limitations of various proposed criteria have been carefully evaluated [49]. The 2 most interesting are the PSI [42] and the British Thoracic Society (BTS) criteria [39, 45]. The PSI is based on derivation and validation cohorts of 14,199 and 38,039 hospitalized patients with CAP, respectively, plus an additional 2287 combined inpatients and outpatients [42]. The PSI stratifies patients into 5 mortality risk classes, and its ability to predict mortality has been confirmed in multiple subsequent studies. On the basis of associated mortality rates, it has been suggested that risk class I and II patients should be treated as outpatients, risk class III patients should be treated in an observation unit or with a short hospitalization, and risk class IV and V patients should be treated as inpatients [42]. Yealy et al. [50] conducted a cluster-randomized trial of low-, moderate-, and high-intensity processes of guideline implementation in 32 EDs in the United States. Their guideline used the PSI for admission decision support and included recommendations for antibiotic therapy, timing of first antibiotic dose, measurement of oxygen saturation, and blood cultures for admitted patients. EDs with moderate- to high-intensity guideline implementation demonstrated more outpatient treatment of low-risk patients and higher compliance with antibiotic recommendations. No differences were found in mortality rate, rate of hospitalization, median time to return to work or usual activities, or patient satisfaction. This study differs from those reporting a mortality rate difference [19, 21] in that many hospitalized patients with pneumonia were not included. In addition, EDs with low-intensity guideline implementation formed the comparison group, rather than EDs practicing nonguideline, usual pneumonia care. The BTS original criteria of 1987 have subsequently been modified [39, 51]. In the initial study, risk of death was increased 21-fold if a patient, at the time of admission, had at least 2 of the following 3 conditions: tachypnea, diastolic hypotension, and an elevated blood urea nitrogen (BUN) level. These criteria appear to function well except among patients with underlying renal insufficiency and among elderly patients [52, 53]. The most recent modification of the BTS criteria includes 5 easily measurable factors [45]. Multivariate analysis of 1068 patients identified the following factors as indicators of increased mortality: confusion (based on a specific mental test or disorientation to person, place, or time), BUN level >7 mmol/L (20 mg/dL), respiratory rate ⩾30 breaths/min, low blood pressure (systolic, 24 h were excluded, Gram stain showed pneumococci in 63% of sputum specimens, and culture results were positive in 86%. For patients who had received no antibiotics, the Gram stain was read as being consistent with pneumococci in 80% of cases, and sputum culture results were positive in 93%. Although there are favorable reports of the utility of Gram stain [118], a meta-analysis showed a low yield, considering the number of patients with adequate specimens and definitive results [119]. Recent data show that an adequate specimen with a predominant morphotype on Gram stain was found in only 14% of 1669 hospitalized patients with CAP [120]. Higher PSI scores did not predict higher yield. However, a positive Gram stain was highly predictive of a subsequent positive culture result. The benefit of a sputum Gram stain is, therefore, 2-fold. First, it broadens initial empirical coverage for less common etiologies, such as infection with S. aureus or gram-negative organisms. This indication is probably the most important, because it will lead to less inappropriate antibiotic therapy. Second, it can validate the subsequent sputum culture results. Forty percent or more of patients are unable to produce any sputum or to produce sputum in a timely manner [108, 120]. The yield of cultures is substantially higher with endotracheal aspirates, bronchoscopic sampling, or transthoracic needle aspirates [120–126], although specimens obtained after initiation of antibiotic therapy are unreliable and must be interpreted carefully [120, 127, 128]. Interpretation is improved with quantitative cultures of respiratory secretions from any source (sputum, tracheal aspirations, and bronchoscopic aspirations) or by interpretation based on semiquantitative culture results [122, 123, 129]. Because of the significant influence on diagnostic yield and cost effectiveness, careful attention to the details of specimen handling and processing are critical if sputum cultures are obtained. Because the best specimens are collected and processed before antibiotics are given, the time to consider obtaining expectorated sputum specimens from patients with factors listed in table 5 is before initiation of antibiotic therapy. Once again, the best indication for more extensive respiratory tract cultures is severe CAP. Gram stain and culture of endotracheal aspirates from intubated patients with CAP produce different results than expectorated sputum from non-ICU patients [76, 120]. Many of the pathogens in the broader microbiological spectrum of severe CAP are unaffected by a single dose of antibiotics, unlike S. pneumoniae. In addition, an endotracheal aspirate does not require patient cooperation, is clearly a lower respiratory tract sample, and is less likely to be contaminated by oropharyngeal colonizers. Nosocomial tracheal colonization is not an issue if the sample is obtained soon after intubation. Therefore, culture and Gram stain of endotracheal aspirates are recommended for patients intubated for severe CAP. In addition to routine cultures, a specific request for culture of respiratory secretions on buffered charcoal yeast extract agar to isolate Legionella species may be useful in this subset of patients with severe CAP in areas where Legionella is endemic, as well as in patients with a recent travel history [130]. The fact that a respiratory tract culture result is negative does not mean that it has no value. Failure to detect S. aureus or gram-negative bacilli in good-quality specimens is strong evidence against the presence of these pathogens. Growth inhibition by antibiotics is lower with these pathogens than with S. pneumoniae, but specimens obtained after initiation of antibiotic therapy are harder to interpret, with the possibility of colonization. Necrotizing or cavitary pneumonia is a risk for CA-MRSA infection, and sputum samples should be obtained in all cases. Negative Gram stain and culture results should be adequate to withhold or stop treatment for MRSA infection. Severe COPD and alcoholism are major risk factors for infection with P. aeruginosa and other gram-negative pathogens [131]. Once again, Gram stain and culture of an adequate sputum specimen are usually adequate to exclude the need for empirical coverage of these pathogens. A sputum culture in patients with suspected legionnaires disease is important, because the identification of Legionella species implies the possibility of an environmental source to which other susceptible individuals may be exposed. Localized community outbreaks of legionnaires disease might be recognized by clinicians or local health departments because ⩾2 patients might be admitted to the same hospital. However, outbreaks of legionnaires disease associated with hotels or cruise ships [132–134] are rarely detected by individual clinicians, because travelers typically disperse from the source of infection before developing symptoms. Therefore, a travel history should be actively sought from patients with CAP, and Legionella testing should be performed for those who have traveled in the 2 weeks before the onset of symptoms. Urinary antigen tests may be adequate to diagnose and treat an individual, but efforts to obtain a sputum specimen for culture are still indicated to facilitate epidemiologic tracking. The availability of a culture isolate of Legionella dramatically improves the likelihood that an environmental source of Legionella can be identified and remediated [135–137]. The yield of sputum culture is increased to 43%–57% when associated with a positive urinary antigen test result [138, 139]. Attempts to obtain a sample for sputum culture from a patient with a positive pneumococcal urinary antigen test result may be indicated for similar reasons. Patients with a productive cough and positive urinary antigen test results have positive sputum culture results in as many as 40%–80% of cases [140–143]. In these cases, not only can sensitivity testing confirm the appropriate choice for the individual patient, but important data regarding local community antibiotic resistance rates can also be acquired.Other cultures.Patients with pleural effusions >5 cm in height on a lateral upright chest radiograph [111] should undergo thoracentesis to yield material for Gram stain and culture for aerobic and anaerobic bacteria. The yield with pleural fluid cultures is low, but the impact on management decisions is substantial, in terms of both antibiotic choice and the need for drainage. Nonbronchoscopic bronchoalveolar lavage (BAL) in the ED has been studied in a small, randomized trial of intubated patients with CAP [144]. A high percentage (87%) of nonbronchoscopic BAL culture results were positive, even in some patients who had already received their first dose of antibiotics. Unfortunately, tracheal aspirates were obtained from only a third of patients in the control group, but they all were culture positive. Therefore, it is unclear that endotracheal aspirates are inferior to nonbronchoscopic BAL. The use of bronchoscopic BAL, protected specimen brushing, or transthoracic lung aspiration has not been prospectively studied for initial management of patients with CAP [123]. The best indications are for immunocompromised patients with CAP or for patients with CAP in whom therapy failed [101, 145].Antigen tests.Urinary antigen tests are commercially available and have been cleared by the US Food and Drug Administration (FDA) for detection of S. pneumoniae and L. pneumophila serogroup 1 [138, 140, 146–149]. Urinary antigen testing appears to have a higher diagnostic yield in patients with more severe illness [139, 140]. For pneumococcal pneumonia, the principal advantages of antigen tests are rapidity (∼15 min), simplicity, reasonable specificity in adults, and the ability to detect pneumococcal pneumonia after antibiotic therapy has been started. Studies in adults show a sensitivity of 50%–80% and a specificity of >90% [146, 149, 150]. This is an attractive test for detecting pneumococcal pneumonia when samples for culture cannot be obtained in a timely fashion or when antibiotic therapy has already been initiated. Serial specimens from patients with known bacteremia were still positive for pneumococcal urinary antigen in 83% of cases after 3 days of therapy [147]. Comparisons with Gram stain show that these 2 rapidly available tests often do not overlap, with only 28% concordance (25 of 88) among patients when results of either test were positive [140]. Only ∼50% of Binax pneumococcal urinary antigen-positive patients can be diagnosed by conventional methods [140, 150]. Disadvantages include cost (approximately $30 per specimen), although this is offset by increased diagnosis-related group-based reimbursement for coding for pneumococcal pneumonia, and the lack of an organism for in vitro susceptibility tests. False-positive results have been seen in children with chronic respiratory diseases who are colonized with S. pneumoniae [151] and in patients with an episode of CAP within the previous 3 months [152], but they do not appear to be a significant problem in colonized patients with COPD [140, 152]. For Legionella, several urinary antigen assays are available, but all detect only L. pneumophila serogroup 1. Although this particular serogroup accounts for 80%–95% of community-acquired cases of legionnaires disease [138, 153] in many areas of North America, other species and serogroups predominate in specific locales [154, 155]. Prior studies of culture-proven legionnaires disease indicate a sensitivity of 70%–90% and a specificity of nearly 99% for detection of L. pneumophila serogroup 1. The urine is positive for antigen on day 1 of illness and continues to be positive for weeks [138, 150]. The major issue with urinary bacterial antigen detection is whether the tests allow narrowing of empirical antibiotic therapy to a single specific agent. The recommended empirical antibiotic regimens will cover both of these microorganisms. Results of a small observational study suggest that therapy with a macrolide alone is adequate for hospitalized patients with CAP who test positive for L. pneumophila urinary antigen [156]. Further research is needed in this area. In contrast, rapid antigen detection tests for influenza, which can also provide an etiologic diagnosis within 15–30 min, can lead to consideration of antiviral therapy. Test performance varies according to the test used, sample type, duration of illness, and patient age. Most show a sensitivity of 50%–70% in adults and a specificity approaching 100% [157–159]. Advantages include the high specificity, the ability of some assays to distinguish between influenza A and B, the rapidity with which the results can be obtained, the possibly reduced use of antibacterial agents, and the utility of establishing this diagnosis for epidemiologic purposes, especially in hospitalized patients who may require infection control precautions. Disadvantages include cost (approximately $30 per specimen), high rates of false-negative test results, false-positive assays with adenovirus infections, and the fact that the sensitivity is not superior to physician judgment among patients with typical symptoms during an influenza epidemic [157, 158, 160]. Direct fluorescent antibody tests are available for influenza and RSV and require ∼2 h. For influenza virus, the sensitivity is better than with the point-of-care tests (85%–95%). They will detect animal subtypes such as H5N1 and, thus, may be preferred for hospitalized patients [161, 162]. For RSV, direct fluorescent antibody tests are so insensitive (sensitivity, 20%–30%) in adults that they are rarely of value [163].Acute-phase serologic testing.The standard for diagnosis of infection with most atypical pathogens, including Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella species other than L. pneumophila, relies on acute- and convalescent-phase serologic testing. Most studies use a microimmunofluorescence serologic test, but this test shows poor reproducibility [164]. Management of patients on the basis of a single acute-phase titer is unreliable [165], and initial antibiotic therapy will be completed before the earliest time point to check a convalescent-phase specimen.PCR.A new PCR test (BD ProbeTec ET Legionella pneumophila; Becton Dickinson) that will detect all serotypes of L. pneumophila in sputum is now cleared by the FDA, but extensive published clinical experience is lacking. Most PCR reagents for other respiratory pathogens (except Mycobacterium species) are “home grown,” with requirements for use based on compliance with NCCLS criteria for analytical validity [166]. Despite the increasing use of these tests for atypical pathogens [167, 168], a 2001 review by the Centers for Disease Control and Prevention (CDC) of diagnostic assays for detection of C. pneumoniae indicated that, of the 18 PCR reagents, only 4 satisfied the criteria for a validated test [166]. The diagnostic criteria defined in this review are particularly important for use in prospective studies of CAP, because most prior reports used liberal criteria, which resulted in exaggerated rates. For SARS, several PCR assays have been developed, but these tests are inadequate because of high rates of false-negative assays in early stages of infection [169, 170]. Antibiotic Treatment A major goal of therapy is eradication of the infecting organism, with resultant resolution of clinical disease. As such, antimicrobials are a mainstay of treatment. Appropriate drug selection is dependent on the causative pathogen and its antibiotic susceptibility. Acute pneumonia may be caused by a wide variety of pathogens (table 6). However, until more accurate and rapid diagnostic methods are available, the initial treatment for most patients will remain empirical. Recommendations for therapy (table 7) apply to most cases; however, physicians should consider specific risk factors for each patient (table 8). A syndromic approach to therapy (under the assumption that an etiology correlates with the presenting clinical manifestations) is not specific enough to reliably predict the etiology of CAP [172–174]. Even if a microbial etiology is identified, debate continues with regard to pathogen-specific treatment, because recent studies suggest coinfection by atypical pathogens (such as C. pneumoniae, Legionella species, and viruses) and more traditional bacteria [120, 175]. However, the importance of treating multiple infecting organisms has not been firmly established. The majority of antibiotics released in the past several decades have an FDA indication for CAP, making the choice of antibiotics potentially overwhelming. Selection of antimicrobial regimens for empirical therapy is based on prediction of the most likely pathogen(s) and knowledge of local susceptibility patterns. Recommendations are generally for a class of antibiotics rather than a specific drug, unless outcome data clearly favor one drug. Because overall efficacy remains good for many classes of agents, the more potent drugs are given preference because of their benefit in decreasing the risk of selection for antibiotic resistance. Other factors for consideration of specific antimicrobials include pharmacokinetics/pharmacodynamics, compliance, safety, and cost. Likely Pathogens in CAP Although CAP may be caused by a myriad of pathogens, a limited number of agents are responsible for most cases. The emergence of newly recognized pathogens, such as the novel SARS-associated coronavirus [170], continually increases the challenge for appropriate management. Table 6 lists the most common causes of CAP, in decreasing order of frequency of occurrence and stratified for severity of illness as judged by site of care (ambulatory vs. hospitalized). S. pneumoniae is the most frequently isolated pathogen. Other bacterial causes include nontypeable Haemophilus influenzae and Moraxella catarrhalis, generally in patients who have underlying bronchopulmonary disease, and S. aureus, especially during an influenza outbreak. Risks for infection with Enterobacteriaceae species and P. aeruginosa as etiologies for CAP are chronic oral steroid administration or severe underlying bronchopulmonary disease, alcoholism, and frequent antibiotic therapy [79, 131], whereas recent hospitalization would define cases as HCAP. Less common causes of pneumonia include, but are by no means limited to, Streptococcus pyogenes, Neisseria meningitidis, Pasteurella multocida, and H. influenzae type b. The “atypical” organisms, so called because they are not detectable on Gram stain or cultivatable on standard bacteriologic media, include M. pneumoniae, C. pneumoniae, Legionella species, and respiratory viruses. With the exception of Legionella species, these microorganisms are common causes of pneumonia, especially among outpatients. However, these pathogens are not often identified in clinical practice because, with a few exceptions, such as L. pneumophila and influenza virus, no specific, rapid, or standardized tests for their detection exist. Although influenza remains the predominant viral cause of CAP in adults, other commonly recognized viruses include RSV [107], adenovirus, and parainfluenza virus, as well as less common viruses, including human metapneumovirus, herpes simplex virus, varicella-zoster virus, SARS-associated coronavirus, and measles virus. In a recent study of immunocompetent adult patients admitted to the hospital with CAP, 18% had evidence of a viral etiology, and, in 9%, a respiratory virus was the only pathogen identified [176]. Studies that include outpatients find viral pneumonia rates as high as 36% [167]. The frequency of other etiologic agents—for example, M. tuberculosis, Chlamydophila psittaci (psittacosis), Coxiella burnetii (Q fever), Francisella tularensis (tularemia), Bordetella pertussis (whooping cough), and endemic fungi (Histoplasma capsulatum, Coccidioides immitis, Cryptococcus neoformans, and Blastomyces hominis)—is largely determined by the epidemiologic setting (table 8) but rarely exceeds 2%–3% total [113, 177]. The exception may be endemic fungi in the appropriate geographic distribution [100]. The need for specific anaerobic coverage for CAP is generally overestimated. Anaerobic bacteria cannot be detected by diagnostic techniques in current use. Anaerobic coverage is clearly indicated only in the classic aspiration pleuropulmonary syndrome in patients with a history of loss of consciousness as a result of alcohol/drug overdose or after seizures in patients with concomitant gingival disease or esophogeal motility disorders. Antibiotic trials have not demonstrated a need to specifically treat these organisms in the majority of CAP cases. Small-volume aspiration at the time of intubation should be adequately handled by standard empirical severe CAP treatment [178] and by the high oxygen tension provided by mechanical ventilation. Antibiotic Resistance Issues Resistance to commonly used antibiotics for CAP presents another major consideration in choosing empirical therapy. Resistance patterns clearly vary by geography. Local antibiotic prescribing patterns are a likely explanation [179–181]. However, clonal spread of resistant strains is well documented. Therefore, antibiotic recommendations must be modified on the basis of local susceptibility patterns. The most reliable source is state/provincial or municipal health department regional data, if available. Local hospital antibiograms are generally the most accessible source of data but may suffer from small numbers of isolates.Drug-resistant S. pneumoniae (DRSP).The emergence of drug-resistant pneumococcal isolates is well documented. The incidence of resistance appears to have stabilized somewhat in the past few years. Resistance to penicillin and cephalosporins may even be decreasing, whereas macrolide resistance continues to increase [179, 182]. However, the clinical relevance of DRSP for pneumonia is uncertain, and few well-controlled studies have examined the impact of in vitro resistance on clinical outcomes of CAP. Published studies are limited by small sample sizes, biases inherent in observational design, and the relative infrequency of isolates exhibiting high-level resistance [183–185]. Current levels of β-lactam resistance do not generally result in CAP treatment failures when appropriate agents (i.e., amoxicillin, ceftriaxone, or cefotaxime) and doses are used, even in the presence of bacteremia [112, 186]. The available data suggest that the clinically relevant level of penicillin resistance is a MIC of at least 4 mg/L [3]. One report suggested that, if cefuroxime is used to treat pneumococcal bacteremia when the organism is resistant in vitro, the outcome is worse than with other therapies [112]. Other discordant therapies, including penicillin, did not have an impact on mortality. Data exist suggesting that resistance to macrolides [187–189] and older fluoroquinolones (ciprofloxacin and levofloxacin) [180, 190, 191] results in clinical failure. To date, no failures have been reported for the newer fluoroquinolones (moxifloxacin and gemifloxacin). Risk factors for infection with β-lactam-resistant S. pneumoniae include age 65 years, β-lactam therapy within the previous 3 months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, and exposure to a child in a day care center [112, 192–194]. Although the relative predictive value of these risk factors is unclear, recent treatment with antimicrobials is likely the most significant. Recent therapy or repeated courses of therapy with β-lactams, macrolides, or fluoroquinolones are risk factors for pneumococcal resistance to the same class of antibiotic [181, 193, 195, 196]. One study found that use of either a β-lactam or macrolide within the previous 6 months predicted an increased likelihood that, if pneumococcal bacteremia is present, the organism would be penicillin resistant [196]. Other studies have shown that repeated use of fluoroquinolones predicts an increased risk of infection with fluoroquinolone-resistant pneumococci [195, 197]. Whether this risk applies equally to all fluoroquinolones or is more of a concern for less active antipneumococcal agents (levofloxacin and ciprofloxacin) than for more active agents (moxifloxacin and gemifloxacin) is uncertain [190, 197, 198]. Recommendations for the use of highly active agents in patients at risk for infection with DRSP is, therefore, based only in part on efficacy considerations; it is also based on a desire to prevent more resistance from emerging by employing the most potent regimen possible. Although increasing the doses of certain agents (penicillins, cephalosporins, levofloxacin) may lead to adequate outcomes in the majority of cases, switching to more potent agents may lead to stabilization or even an overall decrease in resistance rates [179, 180].CA-MRSA.Recently, an increasing incidence of pneumonia due to CA-MRSA has been observed [199, 200]. CA-MRSA appears in 2 patterns: the typical hospital-acquired strain [80] and, recently, strains that are epidemiologically, genotypically, and phenotypically distinct from hospital-acquired strains [201, 202]. Many of the former may represent HCAP, because these earlier studies did not differentiate this group from typical CAP. The latter are resistant to fewer antimicrobials than are hospital-acquired MRSA strains and often contain a novel type IV SCCmec gene. In addition, most contain the gene for Panton-Valentine leukocidin [200, 202], a toxin associated with clinical features of necrotizing pneumonia, shock, and respiratory failure, as well as formation of abscesses and empyemas. The large majority of cases published to date have been skin infections in children. In a large study of CA-MRSA in 3 communities, 2% of CA-MRSA infections were pneumonia [203]. However, pneumonia in both adults [204] and children has been reported, often associated with preceding influenza. This strain should also be suspected in patients who present with cavitary infiltrates without risk factors for anaerobic aspiration pneumonia (gingivitis and a risk for loss of consciousness, such as seizures or alcohol abuse, or esophogeal motility disorders). Diagnosis is usually straightforward, with high yields from sputum and blood cultures in this characteristic clinical scenario. CA-MRSA CAP remains rare in most communities but is expected to be an emerging problem in CAP treatment. Empirical Antimicrobial Therapy Outpatient treatment.The following regimens are recommended for outpatient treatment on the basis of the listed clinical risks. 15. Previously healthy and no risk factors for DRSP infection: A. A macrolide (azithromycin, clarithromycin, or erythromycin) (strong recommendation; level I evidence) Doxycycline (weak recommendation; level III evidence) 16. Presence of comorbidities, such as chronic heart, lung, liver, or renal disease; diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressing conditions or use of immunosuppressing drugs; use of antimicrobials within the previous 3 months (in which case an alternative from a different class should be selected); or other risks for DRSP infection: A. A respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg]) (strong recommendation; level I evidence) β-lactam plus a macrolide (strong recommendation; level I evidence) (High-dose amoxicillin [e.g., 1 g 3 times daily] or amoxicillin-clavulanate [2 g 2 times daily] is preferred; alternatives include ceftriaxone, cefpodoxime, and cefuroxime [500 mg 2 times daily]; doxycycline [level II evidence] is an alternative to the macrolide.) 17. In regions with a high rate (>25%) of infection with high-level (MIC, ⩾16 µg/mL) macrolide-resistant S. pneumoniae, consider the use of alternative agents listed above in recommendation 16 for any patient, including those without comorbidities. (Moderate recommendation; level III evidence.) The most common pathogens identified from recent studies of mild (ambulatory) CAP were S. pneumoniae, M. pneumoniae, C. pneumoniae, and H. influenzae [177, 205]. Mycoplasma infection was most common among patients 93% of S. pneumoniae and is the preferred β-lactam. Ceftriaxone is an alternative to high-dose amoxicillin when parenteral therapy is feasible. Selected oral cephalosporins (cefpodoxime and cefuroxime) can be used as alternatives [210], but these are less active in vitro than high-dose amoxicillin or ceftriaxone. Agents in the same class as the patient had been receiving previously should not be used to treat patients with recent antibiotic exposure. Telithromycin is the first of the ketolide antibiotics, derived from the macrolide family, and is active against S. pneumoniae that is resistant to other antimicrobials commonly used for CAP (including penicillin, macrolides, and fluoroquinolones). Several CAP trials suggest that telithromycin is equivalent to comparators (including amoxicillin, clarithromycin, and trovafloxacin) [211–214]. There have also been recent postmarketing reports of life-threatening hepatotoxicity [215]. At present, the committee is awaiting further evaluation of the safety of this drug by the FDA before making its final recommendation.Inpatient, non-ICU treatment.The following regimens are recommended for hospital ward treatment. 18. A respiratory fluoroquinolone (strong recommendation; level I evidence) 19. β-lactam plus a macrolide (strong recommendation; level I evidence) (Preferred β-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients; with doxycycline [level III evidence] as an alternative to the macrolide. A respiratory fluoroquinolone should be used for penicillin-allergic patients.) The recommendations of combination treatment with a β-lactam plus a macrolide or monotherapy with a fluoroquinolone were based on retrospective studies demonstrating a significant reduction in mortality compared with that associated with administration of a cephalosporin alone [216–219]. Multiple prospective randomized trials have demonstrated that either regimen results in high cure rates. The major discriminating factor between the 2 regimens is the patient's prior antibiotic exposure (within the past 3 months). Preferred β-lactams are those effective against S. pneumoniae and other common, nonatypical pathogens without being overly broad spectrum. In January 2002, the Clinical Laboratory Standards Institute (formerly the NCCLS) increased the MIC breakpoints for cefotaxime and ceftriaxone for nonmeningeal S. pneumoniae infections. These new breakpoints acknowledge that nonmeningeal infections caused by strains formerly considered to be intermediately susceptible, or even resistant, can be treated successfully with usual doses of these β-lactams [112, 186, 220]. Two randomized, double-blind studies showed ertapenem to be equivalent to ceftriaxone [221, 222]. It also has excellent activity against anaerobic organisms, DRSP, and most Enterobacteriaceae species (including extended-spectrum β-lactamase producers, but not P. aeruginosa). Ertapenem may be useful in treating patients with risks for infection with these pathogens and for patients who have recently received antibiotic therapy. However, clinical experience with this agent is limited. Other “antipneumococcal, antipseudomonal” β-lactam agents are appropriate when resistant pathogens, such as Pseudomonas, are likely to be present. Doxycycline can be used as an alternative to a macrolide on the basis of scant data for treatment of Legionella infections [171, 223, 224]. Two randomized, double-blind studies of adults hospitalized for CAP have demonstrated that parenteral azithromycin alone was as effective, with improved tolerability, as intravenous cefuroxime, with or without intravenous erythromycin [225, 226]. In another study, mortality and readmission rates were similar, but the mean LOS was shorter among patients receiving azithromycin alone than among those receiving other guideline-recommended therapy [227]. None of the 10 patients with erythromycin-resistant S. pneumoniae infections died or was transferred to the ICU, including 6 who received azithromycin alone. Another study showed that those receiving a macrolide alone had the lowest 30-day mortality but were the least ill [219]. Such patients were younger and were more likely to be in lower-risk groups. These studies suggest that therapy with azithromycin alone can be considered for carefully selected patients with CAP with nonsevere disease (patients admitted primarily for reasons other than CAP) and no risk factors for infection with DRSP or gram-negative pathogens. However, the emergence of high rates of macrolide resistance in many areas of the country suggests that this therapy cannot be routinely recommended. Initial therapy should be given intravenously for most admitted patients, but some without risk factors for severe pneumonia could receive oral therapy, especially with highly bioavailable agents such as fluoroquinolones. When an intravenous β-lactam is combined with coverage for atypical pathogens, oral therapy with a macrolide or doxycycline is appropriate for selected patients without severe pneumonia risk factors [228].Inpatient, ICU treatment.The following regimen is the minimal recommended treatment for patients admitted to the ICU. 20. β-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin (level II evidence) or a fluoroquinolone (level I evidence) (strong recommendation) (For penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended.) A single randomized controlled trial of treatment for severe CAP is available. Patients with shock were excluded; however, among the patients with mechanical ventilation, treatment with a fluoroquinolone alone resulted in a trend toward inferior outcome [229]. Because septic shock and mechanical ventilation are the clearest reasons for ICU admission, the majority of ICU patients would still require combination therapy. ICU patients are routinely excluded from other trials; therefore, recommendations are extrapolated from nonsevere cases, in conjunction with case series and retrospective analyses of cohorts with severe CAP. For all patients admitted to the ICU, coverage for S. pneumoniae and Legionella species should be ensured [78, 230] by using a potent antipneumococcal β-lactam and either a macrolide or a fluoroquinolone. Therapy with a respiratory fluoroquinolone alone is not established for severe CAP [229], and, if the patient has concomitant pneumococcal meningitis, the efficacy of fluoroquinolone monotherapy is uncertain. In addition, 2 prospective observational studies [231, 232] and 3 retrospective analyses [233–235] have found that combination therapy for bacteremic pneumococcal pneumonia is associated with lower mortality than monotherapy. The mechanism of this benefit is unclear but was principally found in the patients with the most severe illness and has not been demonstrated in nonbacteremic pneumococcal CAP studies. Therefore, combination empirical therapy is recommended for at least 48 h or until results of diagnostic tests are known. In critically ill patients with CAP, a large number of microorganisms other than S. pneumoniae and Legionella species must be considered. A review of 9 studies that included 890 patients with CAP who were admitted to the ICU demonstrates that the most common pathogens in the ICU population were (in descending order of frequency) S. pneumoniae, Legionella species, H. influenzae, Enterobacteriaceae species, S. aureus, and Pseudomonas species [171]. The atypical pathogens responsible for severe CAP may vary over time but can account collectively for ⩾20% of severe pneumonia episodes. The dominant atypical pathogen in severe CAP is Legionella [230], but some diagnostic bias probably accounts for this finding [78]. The recommended standard empirical regimen should routinely cover the 3 most common pathogens that cause severe CAP, all of the atypical pathogens, and most of the relevant Enterobacteriaceae species. Treatment of MRSA or P. aeruginosa infection is the main reason to modify the standard empirical regimen. The following are additions or modifications to the basic empirical regimen recommended above if these pathogens are suspected. 21. For Pseudomonas infection, use an antipneumococcal, antipseudomonal β-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin (750-mg dose) or the above β-lactam plus an aminoglycoside and azithromycin or the above β-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone. (For penicillin-allergic patients, substitute aztreonam for the above β-lactam.) (Moderate recommendation; level III evidence.) Pseudomonal CAP requires combination treatment to prevent inappropriate initial therapy, just as Pseudomonas nosocomial pneumonia does [131]. Once susceptibilities are known, treatment can be adjusted accordingly. Alternative regimens are provided for patients who may have recently received an oral fluoroquinolone, in whom the aminoglycoside-containing regimen would be preferred. A consistent Gram stain of tracheal aspirate, sputum, or blood is the best indication for Pseudomonas coverage. Other, easier-to-treat gram-negative microorganisms may ultimately be proven to be the causative pathogen, but empirical coverage of Pseudomonas species until culture results are known is least likely to be associated with inappropriate therapy. Other clinical risk factors for infection with Pseudomonas species include structural lung diseases, such as bronchiectasis, or repeated exacerbations of severe COPD leading to frequent steroid and/or antibiotic use, as well as prior antibiotic therapy [131]. These patients do not necessarily require ICU admission for CAP [236], so Pseudomonas infection remains a concern for them even if they are only hospitalized on a general ward. The major risk factor for infection with other serious gram-negative pathogens, such as Klebsiella pneumoniae or Acinetobacter species, is chronic alcoholism. 22. For CA-MRSA infection, add vancomycin or linezolid. (Moderate recommendation; level III evidence.) The best indicator of S. aureus infection is the presence of gram-positive cocci in clusters in a tracheal aspirate or in an adequate sputum sample. The same findings on preliminary results of blood cultures are not as reliable, because of the significant risk of contamination [95]. Clinical risk factors for S. aureus CAP include end-stage renal disease, injection drug abuse, prior influenza, and prior antibiotic therapy (especially with fluoroquinolones [237]). For methicillin-sensitive S. aureus, the empirical combination therapy recommended above, which includes a β-lactam and sometimes a respiratory fluoroquinolone, should be adequate until susceptibility results are available and specific therapy with a penicillinase-resistant semisynthetic penicillin or first-generation cephalosporin can be initiated. Both also offer additional coverage for DRSP. Neither linezolid [241] nor vancomycin [238] is an optimal drug for methicillin-sensitive S. aureus. Although methicillin-resistant strains of S. aureus are still the minority, the excess mortality associated with inappropriate antibiotic therapy [80] would suggest that empirical coverage should be considered when CA-MRSA is a concern. The most effective therapy has yet to be defined. The majority of CA-MRSA strains are more susceptible in vitro to non-β-lactam antimicrobials, including trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolones, than are hospital-acquired strains. Previous experience with TMP-SMX in other types of severe infections (endocarditis and septic thrombophlebitis) suggests that TMP-SMX is inferior to vancomycin [239]. Further experience and study of the adequacy of TMP-SMX for CA-MRSA CAP is clearly needed. Vancomycin has never been specifically studied for CAP, and linezolid has been found to be better than ceftriaxone for bacteremic S. pneumoniae in a nonblinded study [240] and superior to vancomycin in retrospective analysis of studies involving nosocomial MRSA pneumonia [241]. Newer agents for MRSA have recently become available, and others are anticipated. Of the presently available agents, daptomycin should not be used for CAP, and no data on pneumonia are available for tigecycline. A concern with CA-MRSA is necrotizing pneumonia associated with production of Panton-Valentine leukocidin and other toxins. Vancomycin clearly does not decrease toxin production, and the effect of TMP-SMX and fluoroquinolones on toxin production is unclear. Addition of clindamycin or use of linezolid, both of which have been shown to affect toxin production in a laboratory setting [242], may warrant their consideration for treatment of these necrotizing pneumonias [204]. Unfortunately, the emergence of resistance during therapy with clindamycin has been reported (especially in erythromycin-resistant strains), and vancomycin would still be needed for bacterial killing. Pathogens Suspected on the Basis of Epidemiologic Considerations Clinicians should be aware of epidemiologic conditions and/or risk factors that may suggest that alternative or specific additional antibiotics should be considered. These conditions and specific pathogens, with preferred treatment, are listed in tables 8 and 9. Pathogen-Directed Therapy 23. Once the etiology of CAP has been identified on the basis of reliable microbiological methods, antimicrobial therapy should be directed at that pathogen. (Moderate recommendation; level III evidence.) Treatment options may be simplified (table 9) if the etiologic agent is established or strongly suspected. Diagnostic procedures that identify a specific etiology within 24–72 h can still be useful for guiding continued therapy. This information is often available at the time of consideration for a switch from parenteral to oral therapy and may be used to direct specific oral antimicrobial choices. If, for example, an appropriate culture reveals penicillin-susceptible S. pneumoniae, a narrow-spectrum agent (such as penicillin or amoxicillin) may be used. This will, hopefully, reduce the selective pressure for resistance. The major issue with pathogen-specific therapy is management of bacteremic S. pneumoniae CAP. The implications of the observational finding that dual therapy was associated with reduced mortality in bacteremic pneumococcal pneumonia [231–235] are uncertain. One explanation for the reduced mortality may be the presence of undiagnosed coinfection with an atypical pathogen; although reported to occur in 18%–38% of CAP cases in some studies [73, 175], much lower rates of undiagnosed coinfection are found in general [171] and specifically in severe cases [78]. An alternative explanation is the immunomodulatory effects of macrolides [244, 245]. It is important to note that these studies evaluated the effects of initial empirical therapy before the results of blood cultures were known and did not examine effects of pathogen-specific therapy after the results of blood cultures were available. The benefit of combination therapy was also most pronounced in the more severely ill patients [233, 234]. Therefore, discontinuation of combination therapy after results of cultures are known is most likely safe in non-ICU patients. 24. Early treatment (within 48 h of onset of symptoms) with oseltamivir or zanamivir is recommended for influenza A. (Strong recommendation; level I evidence.) 25. Use of oseltamivir and zanamivir is not recommended for patients with uncomplicated influenza with symptoms for >48 h (level I evidence), but these drugs may be used to reduce viral shedding in hospitalized patients or for influenza pneumonia. (Moderate recommendation; level III evidence.) Studies that demonstrate that treatment of influenza is effective only if instituted within 48 h of the onset of symptoms have been performed only in uncomplicated cases [246–249]. The impact of such treatment on patients who are hospitalized with influenza pneumonia or a bacterial pneumonia complicating influenza is unclear. In hospitalized adults with influenza, a minority of whom had radiographically documented pneumonia, no obvious benefit was found in one retrospective study of amantadine treatment [250]. Treatment of antigen- or culture-positive patients with influenza with antivirals in addition to antibiotics is warranted, even if the radiographic infiltrate is caused by a subsequent bacterial superinfection. Because of the longer period of persistent positivity after infection, the appropriate treatment for patients diagnosed with only 1 of the rapid diagnostic tests is unclear. Because such patients often have recoverable virus (median duration of 4 days) after hospitalization, antiviral treatment seems reasonable from an infection-control standpoint alone. Because of its broad influenza spectrum, low risk of resistance emergence, and lack of bronchospasm risk, oseltamivir is an appropriate choice for hospitalized patients. The neuraminidase inhibitors are effective against both influenza A and B viruses, whereas the M2 inhibitors, amantadine, and rimantadine are active only against influenza A [251]. In addition, viruses recently circulating in the United States and Canada are often resistant to the M2 inhibitors on the basis of antiviral testing [252, 253]. Therefore, neither amantadine nor rimantadine should be used for treatment or chemoprophylaxis of influenza A in the United States until susceptibility to these antiviral medications has been reestablished among circulating influenza A viruses [249]. Early treatment of influenza in ambulatory adults with inhaled zanamivir or oral oseltamivir appears to reduce the likelihood of lower respiratory tract complications [254–256]. The use of influenza antiviral medications appears to reduce the likelihood of respiratory tract complications, as reflected by reduced usage rates of antibacterial agents in ambulatory patients with influenza. Although clearly important in outpatient pneumonia, this experience may also apply to patients hospitalized primarily for influenza. Parenteral acyclovir is indicated for treatment of varicella-zoster virus infection [257] or herpes simplex virus pneumonia. No antiviral treatment of proven value is available for other viral pneumonias—that is, parainfluenza virus, RSV, adenovirus, metapneumovirus, the SARS agent, or hantavirus. For all patients with viral pneumonias, a high clinical suspicion of bacterial superinfection should be maintained.Pandemic influenza. 26. Patients with an illness compatible with influenza and with known exposure to poultry in areas with previous H5N1 infection should be tested for H5N1 infection. (Moderate recommendation; level III evidence.) 27. In patients with suspected H5N1 infection, droplet precautions and careful routine infection control measures should be used until an H5N1 infection is ruled out. (Moderate recommendation; level III evidence.) 28. Patients with suspected H5N1 infection should be treated with oseltamivir (level II evidence) and antibacterial agents targeting S. pneumoniae and S. aureus, the most common causes of secondary bacterial pneumonia in patients with influenza (level III evidence). (Moderate recommendation.) Recent human infections caused by avian influenza A (H5N1) in Vietnam, Thailand, Cambodia, China, Indonesia, Egypt, and Turkey raise the possibility of a pandemic in the near future. The severity of H5N1 infection in humans distinguishes it from that caused by routine seasonal influenza. Respiratory failure requiring hospitalization and intensive care has been seen in the majority of the >140 recognized cases, and mortality is ∼50% [258, 259]. If a pandemic occurs, deaths will result from primary influenza pneumonia with or without secondary bacterial pneumonia. This section highlights issues for consideration, recognizing that treatment recommendations will likely change as the pandemic progresses. More specific guidance can be found on the IDSA, ATS, CDC, and WHO Web sites as the key features of the pandemic become clearer. Additional guidance is available at http://www.pandemicflu.gov. The WHO has delineated 6 phases of an influenza pandemic, defined by increasing levels of risk and public health response [260]. During the current pandemic alert phase (phase 3: cases of novel influenza infection without sustained person-to-person transmission), testing should be focused on confirming all suspected cases in areas where H5N1 infection has been documented in poultry and on detecting the arrival of the pandemic strain in unaffected countries. Early clinical features of H5N1 infection include persistent fever, cough, and respiratory difficulty progressing over 3–5 days, as well as lymphopenia on admission to the hospital [258, 259, 261]. Exposure to sick and dying poultry in an area with known or suspected H5N1 activity has been reported by most patients, although the recognition of poultry outbreaks has sometimes followed the recognition of human cases [261]. Rapid bedside tests to detect influenza A have been used as screening tools for avian influenza in some settings. Throat swabs tested by RT-PCR have been the most sensitive for confirming H5N1 infection to date, but nasopharyngeal swabs, washes, and aspirates; BAL fluid; lung and other tissues; and stool have yielded positive results by RT-PCR and viral culture with varying sensitivity. Convalescent-phase serum can be tested by microneutralization for antibodies to H5 antigen in a small number of international reference laboratories. Specimens from suspected cases of H5N1 infection should be sent to public health laboratories with appropriate biocontainment facilities; the case should be discussed with health department officials to arrange the transfer of specimens and to initiate an epidemiologic evaluation. During later phases of an ongoing pandemic, testing may be necessary for many more patients, so that appropriate treatment and infection control decisions can be made, and to assist in defining the extent of the pandemic. Recommendations for such testing will evolve on the basis of the features of the pandemic, and guidance should be sought from the CDC and WHO Web sites (http://www.cdc.gov and http://www.who.int). Patients with confirmed or suspected H5N1 influenza should be treated with oseltamivir. Most H5N1 isolates since 2004 have been susceptible to the neuraminidase inhibitors oseltamivir and zanamivir and resistant to the adamantanes (amantidine and rimantidine) [262, 263]. The current recommendation is for a 5-day course of treatment at the standard dosage of 75 mg 2 times daily. In addition, droplet precautions should be used for patients with suspected H5N1 influenza, and they should be placed in respiratory isolation until that etiology is ruled out. Health care personnel should wear N-95 (or higher) respirators during medical procedures that have a high likelihood of generating infectious respiratory aerosols. Bacterial superinfections, particularly pneumonia, are important complications of influenza pneumonia. The bacterial etiologies of CAP after influenza infection have included S. pneumoniae, S. aureus, H. influenzae, and group A streptococci. Legionella, Chlamydophila, and Mycoplasma species are not important causes of secondary bacterial pneumonia after influenza. Appropriate agents would therefore include cefotaxime, ceftriaxone, and respiratory fluoroquinolones. Treatment with vancomycin, linezolid, or other agents directed against CA-MRSA should be limited to patients with confirmed infection or a compatible clinical presentation (shock and necrotizing pneumonia). Because shortages of antibacterials and antivirals are anticipated during a pandemic, the appropriate use of diagnostic tests will be even more important to help target antibacterial therapy whenever possible, especially for patients admitted to the hospital. Time to First Antibiotic Dose 29. For patients admitted through the ED, the first antibiotic dose should be administered while still in the ED. (Moderate recommendation; level III evidence.) Time to first antibiotic dose for CAP has recently received significant attention from a quality-of-care perspective. This emphasis is based on 2 retrospective studies of Medicare beneficiaries that demonstrated statistically significantly lower mortality among patients who received early antibiotic therapy [109, 264]. The initial study suggested a breakpoint of 8 h [264], whereas the subsequent analysis found that 4 h was associated with lower mortality [109]. Studies that document the time to first antibiotic dose do not consistently demonstrate this difference, although none had as large a patient population. Most importantly, prospective trials of care by protocol have not demonstrated a survival benefit to increasing the percentage of patients with CAP who receive antibiotics within the first 4–8 h [22, 65]. Early antibiotic administration does not appear to shorten the time to clinical stability, either [265], although time of first dose does appear to correlate with LOS [266, 267]. A problem of internal consistency is also present, because, in both studies [109, 264], patients who received antibiotics in the first 2 h after presentation actually did worse than those who received antibiotics 2–4 h after presentation. For these and other reasons, the committee did not feel that a specific time window for delivery of the first antibiotic dose should be recommended. However, the committee does feel that therapy should be administered as soon as possible after the diagnosis is considered likely. Conversely, a delay in antibiotic therapy has adverse consequences in many infections. For critically ill, hemodynamically unstable patients, early antibiotic therapy should be encouraged, although no prospective data support this recommendation. Delay in beginning antibiotic treatment during the transition from the ED is not uncommon. Especially with the frequent use of once-daily antibiotics for CAP, timing and communication issues may result in patients not receiving antibiotics for >8 h after hospital admission. The committee felt that the best and most practical resolution to this issue was that the initial dose be given in the ED [22]. Data from the Medicare database indicated that antibiotic treatment before hospital admission was also associated with lower mortality [109]. Given that there are even more concerns regarding timing of the first dose of antibiotic when the patient is directly admitted to a busy inpatient unit, provision of the first dose in the physician's office may be best if the recommended oral or intramuscular antibiotics are available in the office. Switch from Intravenous to Oral Therapy 30. Patients should be switched from intravenous to oral therapy when they are hemodynamically stable and improving clinically, are able to ingest medications, and have a normally functioning gastrointestinal tract. (Strong recommendation; level II evidence.) 31. Patients should be discharged as soon as they are clinically stable, have no other active medical problems, and have a safe environment for continued care. Inpatient observation while receiving oral therapy is not necessary. (Moderate recommendation; level II evidence.) With the use of a potent, highly bioavailable antibiotic, the ability to eat and drink is the major consideration for switching from intravenous to oral antibiotic therapy for non-ICU patients. Initially, Ramirez et al. [268] defined a set of criteria for an early switch from intravenous to oral therapy (table 10). In general, as many as two-thirds of all patients have clinical improvement and meet criteria for a therapy switch in the first 3 days, and most non-ICU patients meet these criteria by day 7. Subsequent studies have suggested that even more liberal criteria are adequate for the switch to oral therapy. An alternative approach is to change from intravenous to oral therapy at a predetermined time, regardless of the clinical response [269]. One study population with nonsevere illness was randomized to receive either oral therapy alone or intravenous therapy, with the switch occurring after 72 h without fever. The study population with severe illness was randomized to receive either intravenous therapy with a switch to oral therapy after 2 days or a full 10-day course of intravenous antibiotics. Time to resolution of symptoms for the patients with nonsevere illness was similar with either regimen. Among patients with more severe illness, the rapid switch to oral therapy had the same rate of treatment failure and the same time to resolution of symptoms as prolonged intravenous therapy. The rapid-switch group required fewer inpatient days (6 vs. 11), although this was likely partially a result of the protocol, but the patients also had fewer adverse events. The need to keep patients in the hospital once clinical stability is achieved has been questioned, even though physicians commonly choose to observe patients receiving oral therapy for ⩾1 day. Even in the presence of pneumococcal bacteremia, a switch to oral therapy can be safely done once clinical stability is achieved and prolonged intravenous therapy is not needed [270]. Such patients generally take longer (approximately half a day) to become clinically stable than do nonbacteremic patients. The benefits of in-hospital observation after a switch to oral therapy are limited and add to the cost of care [32]. Discharge should be considered when the patient is a candidate for oral therapy and when there is no need to treat any comorbid illness, no need for further diagnostic testing, and no unmet social needs [32, 271, 272]. Although it is clear that clinically stable patients can be safely switched to oral therapy and discharged, the need to wait for all of the features of clinical stability to be present before a patient is discharged is uncertain. For example, not all investigators have found it necessary to have the white blood cell count improve. Using the definition for clinical stability in table 10, Halm et al. [273] found that 19.1% of 680 patients were discharged from the hospital with ⩾1 instability. Death or readmission occurred in 10.5% of patients with no instability on discharge, in 13.7% of patients with 1 instability, and in 46.2% with ⩾2 instabilities. In general, patients in higher PSI classes take longer to reach clinical stability than do patients in lower risk classes [274]. This finding may reflect the fact that elderly patients with multiple comorbidities often recover more slowly. Arrangements for appropriate follow-up care, including rehabilitation, should therefore be initiated early for these patients. In general, when switching to oral antibiotics, either the same agent as the intravenous antibiotic or the same drug class should be used. Switching to a different class of agents simply because of its high bioavailability (such as a fluoroquinolone) is probably not necessary for a responding patient. For patients who received intravenous β-lactam-macrolide combination therapy, a switch to a macrolide alone appears to be safe for those who do not have DRSP or gram-negative enteric pathogens isolated [275]. Duration of Antibiotic Therapy 32. Patients with CAP should be treated for a minimum of 5 days (level I evidence), should be afebrile for 48–72 h, and should have no more than 1 CAP-associated sign of clinical instability (table 10) before discontinuation of therapy (level II evidence). (Moderate recommendation.) 33. A longer duration of therapy may be needed if initial therapy was not active against the identified pathogen or if it was complicated by extrapulmonary infection, such as meningitis or endocarditis. (Weak recommendation; level III evidence.) Most patients with CAP have been treated for 7–10 days or longer, but few well-controlled studies have evaluated the optimal duration of therapy for patients with CAP, managed in or out of the hospital. Available data on short-course treatment do not suggest any difference in outcome with appropriate therapy in either inpatients or outpatients [276]. Duration is also difficult to define in a uniform fashion, because some antibiotics (such as azithromycin) are administered for a short time yet have a long half-life at respiratory sites of infection. In trials of antibiotic therapy for CAP, azithromycin has been used for 3–5 days as oral therapy for outpatients, with some reports of single-dose therapy for patients with atypical pathogen infections [276–278]. Results with azithromycin should not be extrapolated to other drugs with significantly shorter half-lives. The ketolide telithromycin has been used for 5–7 days to treat outpatients, including some with pneumococcal bacteremia or PSI classes ⩾III [211]. In a recent study, high-dose (750 mg) levofloxacin therapy for 5 days was equally successful and resulted in more afebrile patients by day 3 than did the 500-mg dose for 7–10 days (49.1% vs. 38.5%; P = .03) [276]. On the basis of these studies, 5 days appears to be the minimal overall duration of therapy documented to be effective in usual forms of CAP. As is discussed above, most patients become clinically stable within 3–7 days, so longer durations of therapy are rarely necessary. Patients with persistent clinical instability are often readmitted to the hospital and may not be candidates for short-duration therapy. Short-duration therapy may be suboptimal for patients with bacteremic S. aureus pneumonia (because of the risk of associated endocarditis and deep-seated infection), for those with meningitis or endocarditis complicating pneumonia, and for those infected with other, less common pathogens (e.g., Burkholderia pseudomallei or endemic fungi). An 8-day course of therapy for nosocomial P. aeruginosa pneumonia led to relapse more commonly than did a 15-day course of therapy [279]. Whether the same results would be applicable to CAP cases is unclear, but the presence of cavities or other signs of tissue necrosis may warrant prolonged treatment. Studies of duration of therapy have focused on patients receiving empirical treatment, and reliable data defining treatment duration after an initially ineffective regimen are lacking. Other Treatment Considerations 34. Patients with CAP who have persistent septic shock despite adequate fluid resuscitation should be considered for treatment with drotrecogin alfa activated within 24 h of admission. (Weak recommendation, level II evidence.) Drotrecogin alfa activated is the first immunomodulatory therapy approved for severe sepsis. In the United States, the FDA recommended the use of drotrecogin alfa activated for patients at high risk of death. The high-risk criterion suggested by the FDA was an Acute Physiologic and Chronic Health Assessment (APACHE) II score ⩾25, based on a subgroup analysis of the overall study. However, the survival advantage (absolute risk reduction, 9.8%) of drotrecogin alfa activated treatment of patients in the CAP subgroup was equivalent to that in the subgroup with APACHE II scores ⩾25 [92, 280, 281]. The greatest reduction in the mortality rate was for S. pneumoniae infection (relative risk, 0.56; 95% CI, 0.35–0.88) [282]. Subsequent data have suggested that the benefit appears to be greatest when the treatment is given as early in the hospital admission as possible. In the subgroup with severe CAP caused by a pathogen other than S. pneumoniae and treated with appropriate antibiotics, there was no evidence that drotrecogin alfa activated affected mortality. Although the benefit of drotrecogin alfa activated is clearly greatest for patients with CAP who have high APACHE II scores, this criterion alone may not be adequate to select appropriate patients. An APACHE II score ⩾25 was selected by a subgroup analysis of the entire study cohort and may not be similarly calibrated in a CAP-only cohort. Two-organ failure, the criterion suggested for drotrecogin alfa activated use by the European regulatory agency, did not influence the mortality benefit for patients with CAP [92]. Therefore, in addition to patients with septic shock, other patients with severe CAP could be considered for treatment with drotrecogin alfa activated. Those with sepsis-induced leukopenia are at extremely high risk of death and ARDS and are, therefore, potential candidates. Conversely, the benefit of drotrecogin alfa activated is not as clear when respiratory failure is caused more by exacerbation of underlying lung disease rather than by the pneumonia itself. Other minor criteria for severe CAP proposed above are similar to organ failure criteria used in many sepsis trials. Consideration of treatment with drotrecogin alfa activated is appropriate, but the strength of the recommendation is only level II. 35. Hypotensive, fluid-resuscitated patients with severe CAP should be screened for occult adrenal insufficiency. (Moderate recommendation; level II evidence.) A large, multicenter trial has suggested that stress-dose (200–300 mg of hydrocortisone per day or equivalent) steroid treatment improves outcomes of vasopressor-dependent patients with septic shock who do not have an appropriate cortisol response to stimulation [283]. Once again, patients with CAP made up a significant fraction of patients entered into the trial. In addition, 3 small pilot studies have suggested that there is a benefit to corticosteroid therapy even for patients with severe CAP who are not in shock [284–286]. The small sample size and baseline differences between groups compromise the conclusions. Although the criteria for steroid replacement therapy remain controversial, the frequency of intermittent steroid treatment in patients at risk for severe CAP, such as those with severe COPD, suggests that screening of patients with severe CAP is appropriate with replacement if inadequate cortisol levels are documented. If corticosteroids are used, close attention to tight glucose control is required [287]. 36. Patients with hypoxemia or respiratory distress should receive a cautious trial of noninvasive ventilation (NIV) unless they require immediate intubation because of severe hypoxemia (arterial oxygen pressure/fraction of inspired oxygen [PaO2/FiO2] ratio, 25% absolute risk reduction for the need for intubation [114]. The use of NIV may also improve intermediate-term mortality. Inability to expectorate may limit the use of NIV [290], but intermittent application of NIV may allow for its use in patients with productive cough unless sputum production is excessive. Prompt recognition of a failed NIV trial is critically important, because most studies demonstrate worse outcomes for patients who require intubation after a prolonged NIV trial [288, 290]. Within the first 1–2 h of NIV, failure to improve respiratory rate and oxygenation [114, 289, 290] or failure to decrease carbon dioxide partial pressure (pCO2) in patients with initial hypercarbia [114] predicts NIV failure and warrants prompt intubation. NIV provides no benefit for patients with ARDS [289], which may be nearly indistinguishable from CAP among patients with bilateral alveolar infiltrates. Patients with CAP who have severe hypoxemia (PaO2/FiO2 ratio, 72 h after initial treatment is often related to intercurrent complications, deterioration in underlying disease, or development of nosocomial superinfection. The second pattern is that of persistent or nonresponding pneumonia. Nonresponse can be defined as absence of or delay in achieving clinical stability, using the criteria in table 10 [274, 294]. When these criteria were used, the median time to achieve clinical stability was 3 days for all patients, but a quarter of patients took ⩾6 days to meet all of these criteria for stability [274]. Stricter definitions for each of the criteria and higher PSI scores were associated with longer times to achieve clinical stability. Conversely, subsequent transfer to the ICU after achieving this degree of clinical stability occurred in 30 days after initial pneumonia-like syndrome [298]. As many as 20% of these patients will be found to have diseases other than CAP when carefully evaluated [295]. Two studies have evaluated the risk factors for a lack of response in multivariate analyses [81, 84], including those amenable to medical intervention. Use of fluoroquinolones was independently associated with a better response in one study [84], whereas discordant antimicrobial therapy was associated with early failure [81]. In table 12, the different risk and protective factors and their respective odds ratios are summarized. Specific causes that may be responsible for a lack of response in CAP have been classified by Arancibia et al. [101] (table 11). This classification may be useful for clinicians as a systematic approach to diagnose the potential causes of nonresponse in CAP. Although in the original study only 8 (16%) of 49 cases could not be classified [101], a subsequent prospective multicenter trial found that the cause of failure could not be determined in 44% [84].Management of nonresponding CAP.Nonresponse to antibiotics in CAP will generally result in ⩾1 of 3 clinical responses: (1) transfer of the patient to a higher level of care, (2) further diagnostic testing, and (3) escalation or change in treatment. Issues regarding hospital admission and ICU transfer are discussed above. An inadequate host response, rather than inappropriate antibiotic therapy or unexpected microorganisms, is the most common cause of apparent antibiotic failure when guideline-recommended therapy is used. Decisions regarding further diagnostic testing and antibiotic change/escalation are intimately intertwined and need to be discussed in tandem. Information regarding the utility of extensive microbiological testing in cases of nonresponding CAP is mainly retrospective and therefore affected by selection bias. A systematic diagnostic approach, which included invasive, noninvasive, and imaging procedures, in a series of nonresponding patients with CAP obtained a specific diagnosis in 73% [101]. In a different study, mortality among patients with microbiologically guided versus empirical antibiotic changes was not improved (mortality rate, 67% vs. 64%, respectively) [76]. However, no antibiotic changes were based solely on sputum smears, suggesting that invasive cultures or nonculture methods may be needed. Mismatch between the susceptibility of a common causative organism, infection with a pathogen not covered by the usual empirical regimen, and nosocomial superinfection pneumonia are major causes of apparent antibiotic failure. Therefore, the first response to nonresponse or deterioration is to reevaluate the initial microbiological results. Culture or sensitivity data not available at admission may now make the cause of clinical failure obvious. In addition, a further history of any risk factors for infection with unusual microorganisms (table 8) should be taken if not done previously. Viruses are relatively neglected as a cause of infection in adults but may account for 10%–20% of cases [299]. Other family members or coworkers may have developed viral symptoms in the interval since the patient was admitted, increasing suspicion of this cause. The evaluation of nonresponse is severely hampered if a microbiological diagnosis was not made on initial presentation. If cultures were not obtained, clinical decisions are much more difficult than if the adequate cultures were obtained but negative. Risk factors for nonresponse or deterioration (table 12), therefore, figure prominently in the list of situations in which more aggressive initial diagnostic testing is warranted (table 5). Blood cultures should be repeated for deterioration or progressive pneumonia. Deteriorating patients have many of the risk factors for bacteremia, and blood cultures are still high yield even in the face of prior antibiotic therapy [95]. Positive blood culture results in the face of what should be adequate antibiotic therapy should increase the suspicion of either antibiotic-resistant isolates or metastatic sites, such as endocarditis or arthritis. Despite the high frequency of infectious pulmonary causes of nonresponse, the diagnostic utility of respiratory tract cultures is less clear. Caution in the interpretation of sputum or tracheal aspirate cultures, especially of gram-negative bacilli, is warranted because early colonization, rather than superinfection with resistant bacteria, is not uncommon in specimens obtained after initiation of antibiotic treatment. Once again, the absence of multidrug-resistant pathogens, such as MRSA or Pseudomonas, is strong evidence that they are not the cause of nonresponse. An etiology was determined by bronchoscopy in 44% of patients with CAP, mainly in those not responding to therapy [300]. Despite the potential benefit suggested by these results, and in contrast to ventilator-associated pneumonia [301, 302], no randomized study has compared the utility of invasive versus noninvasive strategies in the CAP population with nonresponse. Rapid urinary antigen tests for S. pneumoniae and L. pneumophila remain positive for days after initiation of antibiotic therapy [147, 152] and, therefore, may be high-yield tests in this group. A urinary antigen test result that is positive for L. pneumophila has several clinical implications, including that coverage for Legionella should be added if not started empirically [81]. This finding may be a partial explanation for the finding that fluoroquinolones are associated with a lower incidence of nonresponse [84]. If a patient has persistent fever, the faster response to fluoroquinolones in Legionella CAP warrants consideration of switching coverage from a macrolide [303]. Stopping the β-lactam component of combination therapy to exclude drug fever is probably also safe [156]. Because one of the major explanations for nonresponse is poor host immunity rather than incorrect antibiotics, a positive pneumococcal antigen test result would at least clarify the probable original pathogen and turn attention to other causes of failure. In addition, a positive pneumococcal antigen test result would also help with interpretation of subsequent sputum/tracheal aspirate cultures, which may indicate early superinfection. Nonresponse may also be mimicked by concomitant or subsequent extrapulmonary infection, such as intravascular catheter, urinary, abdominal, and skin infections, particularly in ICU patients. Appropriate cultures of these sites should be considered for patients with nonresponse to CAP therapy. In addition to microbiological diagnostic procedures, several other tests appear to be valuable for selected patients with nonresponse: Chest CT. In addition to ruling out pulmonary emboli, a CT scan can disclose other reasons for antibiotic failure, including pleural effusions, lung abscess, or central airway obstruction. The pattern of opacities may also suggest alternative noninfectious disease, such as bronchiolitis obliterans organizing pneumonia. Thoracentesis. Empyema and parapneumonic effusions are important causes of nonresponse [81, 101], and thoracentesis should be performed whenever significant pleural fluid is present. Bronchoscopy with BAL and transbronchial biopsies. If the differential of nonresponse includes noninfectious pneumonia mimics, bronchoscopy will provide more diagnostic information than routine microbiological cultures. BAL may reveal noninfectious entities, such as pulmonary hemorrhage or acute eosinophilic pneumonia, or hints of infectious diseases, such as lymphocytic rather than neutrophilic alveolitis pointing toward virus or Chlamydophila infection. Transbronchial biopsies can also yield a specific diagnosis. Antibiotic management of nonresponse in CAP has not been studied. The overwhelming majority of cases of apparent nonresponse are due to the severity of illness at presentation or a delay in treatment response related to host factors. Other than the use of combination therapy for severe bacteremic pneumococcal pneumonia [112, 231, 233, 234], there is no documentation that additional antibiotics for early deterioration lead to a better outcome. The presence of risk factors for potentially untreated microorganisms may warrant temporary empirical broadening of the antibiotic regimen until results of diagnostic tests are available. Prevention 39. All persons ⩾50 years of age, others at risk for influenza complications, household contacts of high-risk persons, and health care workers should receive inactivated influenza vaccine as recommended by the Advisory Committee on Immunization Practices (ACIP), CDC. (Strong recommendation; level I evidence.) 40. The intranasally administered live attenuated vaccine is an alternative vaccine formulation for some persons 5–49 years of age without chronic underlying diseases, including immunodeficiency, asthma, or chronic medical conditions. (Strong recommendation; level I evidence.) 41. Health care workers in inpatient and outpatient settings and long-term care facilities should receive annual influenza immunization. (Strong recommendation; level I evidence.) 42. Pneumococcal polysaccharide vaccine is recommended for persons ⩾65 years of age and for those with selected high-risk concurrent diseases, according to current ACIP guidelines. (Strong recommendation; level II evidence.) Vaccines targeting pneumococcal disease and influenza remain the mainstay for preventing CAP. Pneumococcal polysaccharide vaccine and inactivated influenza vaccine are recommended for all older adults and for younger persons with medical conditions that place them at high risk for pneumonia morbidity and mortality (table 13) [304, 305]. The new live attenuated influenza vaccine is recommended for healthy persons 5–49 years of age, including health care workers [304]. Postlicensure epidemiologic studies have documented the effectiveness of pneumococcal polysaccharide vaccines for prevention of invasive infection (bacteremia and meningitis) among elderly individuals and younger adults with certain chronic medical conditions [306–309]. The overall effectiveness against invasive pneumococcal disease among persons ⩾65 years of age is 44%–75% [306, 308, 310], although efficacy may decrease with advancing age [308]. The effectiveness of the vaccine against pneumococcal disease in immunocompromised persons is less clear, and results of studies evaluating its effectiveness against pneumonia without bacteremia have been mixed. The vaccine has been shown to be cost effective for general populations of adults 50–64 years of age and ⩾65 years of age [311, 312]. A second dose of pneumococcal polysaccharide vaccine after a ⩾5-year interval has been shown to be safe, with only slightly more local reactions than are seen after the first dose [313]. Because the safety of a third dose has not been demonstrated, current guidelines do not suggest repeated revaccination. The pneumococcal conjugate vaccine is under investigation for use in adults but is currently only licensed for use in young children [314, 315]. However, its use in children <5 years of age has dramatically reduced invasive pneumococcal bacteremia among adults as well [314, 316]. The effectiveness of influenza vaccines depends on host factors and on how closely the antigens in the vaccine are matched with the circulating strain of influenza. A systematic review demonstrates that influenza vaccine effectively prevents pneumonia, hospitalization, and death [317, 318]. A recent large observational study of adults ⩾65 years of age found that vaccination against influenza was associated with a reduction in the risk of hospitalization for cardiac disease (19% reduction), cerebrovascular disease (16%–23% reduction), and pneumonia or influenza (29%–32% reduction) and a reduction in the risk of death from all causes (48%–50% reduction) [319]. In long-term-care facilities, vaccination of health care workers with influenza vaccine is an important preventive health measure [318, 320, 321]. Because the main virulence factors of influenza virus, a neuraminidase and hemagglutinin, adapt quickly to selective pressures, new vaccine formulations are created each year on the basis of the strains expected to be circulating, and annual revaccination is needed for optimal protection. 43. Vaccination status should be assessed at the time of hospital admission for all patients, especially those with medical illnesses. (Moderate recommendation; level III evidence.) 44. Vaccination may be performed either at hospital discharge or during outpatient treatment. (Moderate recommendation; level III evidence.) 45. Influenza vaccine should be offered to persons at hospital discharge or during outpatient treatment during the fall and winter. (Strong recommendation; level III evidence.) Many people who should receive either influenza or pneumococcal polysaccharide vaccine have not received them. According to a 2003 survey, only 69% of adults ⩾65 years of age had received influenza vaccine in the past year, and only 64% had ever received pneumococcal polysaccharide vaccine [322]. Coverage levels are lower for younger persons with vaccine indications. Among adults 18–64 years of age with diabetes, 49% had received influenza vaccine, and 37% had ever received pneumococcal vaccine [323]. Studies of vaccine delivery methods indicate that the use of standing orders is the best way to improve vaccination coverage in office, hospital, or long-term care settings [324]. Hospitalization of at-risk patients represents an underutilized opportunity to assess vaccination status and to either provide or recommend immunization. Ideally, patients should be vaccinated before developing pneumonia; therefore, admissions for illnesses other than respiratory tract infections would be an appropriate focus. However, admission for pneumonia is an important trigger for assessing the need for immunization. The actual immunization may be better provided at the time of outpatient follow-up, especially with the emphasis on early discharge of patients with CAP. Patients with an acute fever should not be vaccinated until their fever has resolved. Confusion of a febrile reaction to immunization with recurrent/superinfection pneumonia is a risk. However, immunization at discharge for pneumonia is warranted for patients for whom outpatient follow-up is unreliable, and such vaccinations have been safely given to many patients. The best time for influenza vaccination in North America is October and November, although vaccination in December and later is recommended for those who were not vaccinated earlier. Influenza and pneumococcal vaccines can be given at the same time in different arms. Chemoprophylaxis can be used as an adjunct to vaccination for prevention and control of influenza. Oseltamivir and zanamivir are both approved for prophylaxis; amantadine and rimantadine have FDA indications for chemoprophylaxis against influenza A infection, but these agents are currently not recommended because of the frequency of resistance among strains circulating in the United States and Canada [252, 253]. Developing an adequate immune response to the inactivated influenza vaccine takes ∼2 weeks in adults; chemoprophylaxis may be useful during this period for those with household exposure to influenza, those who live or work in institutions with an influenza outbreak, or those who are at high risk for influenza complications in the setting of a community outbreak [325, 326]. Chemoprophylaxis also may be useful for persons with contraindications to influenza vaccine or as an adjunct to vaccination for those who may not respond well to influenza vaccine (e.g., persons with HIV infection) [325, 326]. The use of influenza antiviral medications for treatment or chemoprophylaxis should not affect the response to the inactivated vaccine. Because it is unknown whether administering influenza antiviral medications affects the performance of the new live attenuated intranasal vaccine, this vaccine should not be used in conjunction with antiviral agents. Other types of vaccination can be considered. Pertussis is a rare cause of pneumonia itself. However, pneumonia is one of the major complications of pertussis. Concern over waning immunity has led the ACIP to emphasize adult immunization for pertussis [327]. One-time vaccination with the new tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine—adsorbed (Tdap) product, ADACEL (Sanofi Pasteur)—is recommended for adults 19–64 years of age. For most adults, the vaccine should be given in place of their next routine tetanus-diphtheria booster; adults with close contact with infants <12 months of age and health care workers should receive the vaccine as soon as possible, with an interval as short as 2 years after their most recent tetanus/diphtheria booster. 46. Smoking cessation should be a goal for persons hospitalized with CAP who smoke. (Moderate recommendation; level III evidence.) 47. Smokers who will not quit should also be vaccinated for both pneumococcus and influenza. (Weak recommendation; level III evidence.) Smoking is associated with a substantial risk of pneumococcal bacteremia; one report showed that smoking was the strongest of multiple risks for invasive pneumococcal disease in immunocompetent nonelderly adults [328]. Smoking has also been identified as a risk for Legionella infection [329]. Smoking cessation should be attempted when smokers are hospitalized; this is particularly important and relevant when these patients are hospitalized for pneumonia. Materials for clinicians and patients to assist with smoking cessation are available online from the US Surgeon General (http://www.surgeongeneral.gov/tobacco), the Centers for Disease Control and Prevention (http://www.cdc.gov/tobacco), and the American Cancer Society (http://www.cancer.org). The most successful approaches to quitting include some combination of nicotine replacement and/or bupropion, a method to change habits, and emotional support. Given the increased risk of pneumonia, the committee felt that persons unwilling to stop smoking should be given the pneumococcal polysaccharide vaccine, although this is not currently an ACIP-recommended indication. 48. Cases of pneumonia that are of public health concern should be reported immediately to the state or local health department. (Strong recommendation; level III evidence.) Public health interventions are important for preventing some forms of pneumonia. Notifying the state or local health department about a condition of interest is the first step to getting public health professionals involved. Rules and regulations regarding which diseases are reportable differ between states. For pneumonia, most states require reporting for legionnaires disease, SARS, and psittacosis, so that an investigation can determine whether others may be at risk and whether control measures are necessary. For legionnaires disease, reporting of cases has helped to identify common-source outbreaks caused by environmental contamination [130]. For SARS, close observation and, in some cases, quarantine of close contacts have been critical for controlling transmission [330]. In addition, any time avian influenza (H5N1) or a possible terrorism agent (e.g., plague, tularemia, or anthrax) is being considered as the etiology of pneumonia, the case should be reported immediately, even before a definitive diagnosis is obtained. In addition, pneumonia cases that are caused by pathogens not thought to be endemic to the area should be reported, even if those conditions are not typically on the list of reportable conditions, because control strategies might be possible. For other respiratory diseases, episodes that are suspected of being part of an outbreak or cluster should be reported. For pneumococcal disease and influenza, outbreaks can occur in crowded settings of susceptible hosts, such as homeless shelters, nursing homes, and jails. In these settings, prophylaxis, vaccination, and infection control methods are used to control further transmission [331]. For Mycoplasma, antibiotic prophylaxis has been used in schools and institutions to control outbreaks [332]. 49. Respiratory hygiene measures, including the use of hand hygiene and masks or tissues for patients with cough, should be used in outpatient settings and EDs as a means to reduce the spread of respiratory infections. (Strong recommendation; level III evidence.) In part because of the emergence of SARS, improved respiratory hygiene measures (“respiratory hygiene” or “cough etiquette”) have been promoted as a means for reducing transmission of respiratory infections in outpatient clinics and EDs [333]. Key components of respiratory hygiene include encouraging patients to alert providers when they present for a visit and have symptoms of a respiratory infection; the use of hand hygiene measures, such as alcohol-based hand gels; and the use of masks or tissues to cover the mouth for patients with respiratory illnesses. In a survey of the US population, the use of masks in outpatient settings was viewed as an acceptable means for reducing the spread of respiratory infections [334]. For hospitalized patients, infection control recommendations typically are pathogen specific. For more details on the use of personal protective equipment and other measures to prevent transmission within health care settings, refer to the Healthcare Infection Control Practices Advisory Committee [335]. Suggested Performance Indicators Performance indicators are tools to help guideline users measure both the extent and the effects of implementation of guidelines. Such tools or measures can be indicators of the process itself, outcomes, or both. Deviations from the recommendations are expected in a proportion of cases, and compliance in 80%–95% of cases is generally appropriate, depending on the indicator. Four specific performance indicators have been selected for the CAP guidelines, 3 of which focus on treatment issues and 1 of which deals with prevention: Initial empirical treatment of CAP should be consistent with guideline recommendations. Data exist that support the role of CAP guidelines and that have demonstrated reductions in cost, LOS, and mortality when the guidelines are followed. Reasons for deviation from the guidelines should be clearly documented in the medical record. The first treatment dose for patients who are to be admitted to the hospital should be given in the ED. Unlike in prior guidelines, a specific time frame is not being recommended. Initiation of treatment would be expected within 6–8 h of presentation whenever the admission diagnosis is likely CAP. A rush to treatment without a diagnosis of CAP can, however, result in the inappropriate use of antibiotics with a concomitant increase in costs, adverse drug events, increased antibiotic selection pressure, and, possibly, increased antibiotic resistance. Consideration should be given to monitoring the number of patients who receive empirical antibiotics in the ED but are admitted to the hospital without an infectious diagnosis. Mortality data for all patients with CAP admitted to wards, ICUs, or high-level monitoring units should be collected. Although tools to predict mortality and severity of illness exist—such as the PSI and CURB-65 criteria, respectively—none is foolproof. Overall mortality rates for all patients with CAP admitted to the hospital, including general medical wards, should be monitored and compared with severity-adjusted norms. In addition, careful attention should be paid to the percentage of patients with severe CAP, as defined in this document, who are admitted initially to a non-ICU or a high-level monitoring unit and to their mortality rate. It is important to determine what percentage of at-risk patients in one's practice actually receive immunization for influenza or pneumococcal infection. Prevention of infection is clearly more desirable than having to treat established infection, but it is clear that target groups are undervaccinated. Trying to increase the number of protected individuals is a desirable end point and, therefore, a goal worth pursuing. This is particularly true for influenza, because the vaccine data are more compelling, but it is important to try to protect against pneumococcal infection as well. Coverage of 90% of adults ⩾65 years of age should be the target.
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            Incidence and characteristics of viral community-acquired pneumonia in adults.

            In adults, viral causes of community-acquired pneumonia (CAP) are poorly characterised. The aims of this study were to characterise the viral aetiology of CAP in adults by using an extensive array of viral diagnostic tests and to compare the characteristics of viral pneumonia with those of pneumococcal pneumonia. Adults admitted to Christchurch Hospital over a 1-year period with CAP were included in the study. Microbiological testing methods included blood and sputum cultures, urinary antigen testing for Streptococcus pneumoniae and Legionella pneumophila, antibody detection in paired sera and detection of respiratory viruses in nasopharyngeal swabs by immunofluorescence, culture and PCR. Of 304 patients with CAP, a viral diagnosis was made in 88 (29%), with rhinoviruses and influenza A being the most common. Two or more pathogens were detected in 49 (16%) patients, 45 of whom had mixed viral and bacterial infections. There were no reliable clinical predictors of viral pneumonia, although several variables were independently associated with some aetiologies. The presence of myalgia was associated with pneumonia caused by any respiratory virus (OR 3.62, 95% CI 1.29 to 10.12) and influenza pneumonia (OR 190.72, 95% CI 3.68 to 9891.91). Mixed rhinovirus/pneumococcal infection was associated with severe disease. Virus-associated CAP is common in adults. Polymicrobial infections involving bacterial and viral pathogens are frequent and may be associated with severe pneumonia.
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              Practice Guidelines for the Management of Community-Acquired Pneumonia in Adults

              Executive Summary Guidelines for the management of community-acquired pneumonia were issued on behalf of the Infectious Diseases Society of America in April 1998. The present version represents a revision of these guidelines issued in February 2000; updates at 6- to 12-month intervals are anticipated. A summary of these guidelines follows. Grading system. Recommendations are categorized by the letters A–D, according to the strength of the recommendation: A, good evidence to support the recommendation; B, moderate evidence to support the recommendation; C, poor evidence to support the recommendation; and D, evidence against the recommendation. The recommendations are also graded by the quality of the evidence to support the recommendation, on the basis of categories I–III; I, at least 1 randomized controlled trial supports the recommendation; II, evidence from at least 1 well-designed clinical trial without randomization supports the recommendation; and III, “expert opinion.” Chest radiography. Chest radiography is considered critical for establishing the diagnosis of pneumonia and for distinguishing this condition from acute bronchitis (AB), which is a common cause of antibiotic abuse. Site of care. Recommendations regarding the decision for hospitalization are based on the methodology used in the clinical prediction rule for short-term mortality, from the publications of the Pneumonia Patient Outcome Research Team (Pneumonia PORT). Patients are stratified into 5 severity classes by means of a 2-step process. Class I indicates an age 20-fold higher than the cost of outpatient treatment. Figure 1 Evaluation for diagnosis and management of community-acquired pneumonia, including site, duration, and type of treatment. β-Lactam: cefotaxime, ceftriaxone, or a β-lactam / β-lactamase inhibitor. Fluoroquinolone: levofloxacin, moxifloxacin, or gatifloxacin or another fluoroquinolone with enhanced antipneumococcal activity. Macrolide: erythromycin, clarithromycin, or azithromycin. CBC, complete blood cell count; ICU, intensive care unit. *Other tests for selected patients: see text, Diagnostic Evaluation: Etiology. **See table 15 for special considerations. Numerous studies have identified risk factors for death in cases of CAP [9, 10, 12]. These factors were well-defined in the pre–penicillin era; studies of adults showed an increased risk with alcohol consumption, increasing age, the presence of leukopenia, the presence of bacteremia, and radiographic changes [12]. More recent studies have confirmed these findings [2, 13–18]. Independent associations with increased mortality have also been demonstrated for a variety of comorbid illnesses, such as active malignancies [10, 16, 19], immunosuppression [20, 21], neurological disease [19, 22, 23], congestive heart failure [10, 17, 19], coronary artery disease [19], and diabetes mellitus [10, 19, 24]. Signs and symptoms independently associated with increased mortality consist of dyspnea [10], chills [25], altered mental status [10, 19, 23, 26], hypothermia or hyperthermia [10, 16, 17, 20], tachypnea [10, 19, 23, 27], and hypotension (diastolic and systolic) [10, 19, 26–28]. Laboratory and radiographic findings independently associated with increased mortality are hyponatremia [10, 19], hyperglycemia [10, 19], azotemia [10, 19, 27, 28], hypoalbuminemia [16, 19, 22, 25], hypoxemia [10, 19], liver function test abnormalities [19], and pleural effusion [29]. Infections due to gram-negative bacilli or S. aureus, postobstructive pneumonia, and aspiration pneumonia are also independently associated with higher mortality [30]. Despite our knowledge regarding the associations of clinical, laboratory, and radiographic factors and patient mortality, there is wide geographic variation in hospital admission rates for CAP [31, 32]. This variation suggests that physicians do not use a uniform strategy to relate the decision to hospitalize to the prognosis. In fact, physicians often overestimate the risk of death for patients with CAP, and the degree of overestimation is independently associated with the decision to hospitalize [30]. Over the past 10 years, at least 13 studies have used multivariate analysis to identify predictors of prognosis for patients with CAP [10, 16–20, 25–27, 33–35]. The Pneumonia PORT developed a methodologically sound clinical prediction rule that quantifies short-term mortality for patients with this illness [10]. Used as a guideline, this rule may help physicians make decisions about the initial location and intensity of treatment for patients with this illness (table 2). Table 2 Comparison of risk class-specific mortality rates in the derivation and validation cohorts. The Pneumonia PORT prediction rule was derived with 14,199 inpatients with CAP; it was independently validated with 38,039 inpatients with CAP and 2287 inpatients and outpatients prospectively enrolled in the Pneumonia PORT cohort study. With this rule, patients are stratified into 5 severity classes by means of a 2-step process. In step 1, patients are classified as risk class I (the lowest severity level) if they are aged ≤50 years, have none of 5 important comorbid conditions (neoplastic disease, liver disease, congestive heart failure, cerebrovascular disease, or renal disease), and have normal or only mildly deranged vital signs and normal mental status. In step 2, all patients who are not assigned to risk class I on the basis of the initial history and physical examination findings alone are stratified into classes II–V, on the basis of points assigned for 3 demographic variables (age, sex, and nursing home residence), 5 comorbid conditions (listed above), 5 physical examination findings (altered mental status, tachypnea, tachycardia, systolic hypotension, hypothermia, or hyperthermia), and 7 laboratory or radiographic findings (acidemia, elevated blood urea nitrogen, hyponatremia, hyperglycemia, anemia, hypoxemia, or pleural effusion; table 3). Point assignments correspond with the following classes: ≤70, class II; 71–90, class III; 91–130, class IV; and >130, class V. Table 3 Scoring system for step 2 of the prediction rule: assignment to risk classes II–V In the derivation and validation of this rule, mortality was low for risk classes I–III (0.1%–2.8%), intermediate for class IV (8.2%–9.3%), and high for class V (27.0%–31.1%). Increases in risk class were also associated with subsequent hospitalization and delayed return to usual activities for outpatients and with rates of admission to the ICU and length of stay for inpatients in the Pneumonia PORT validation cohort. On the basis of these observations, Pneumonia PORT investigators suggest that patients in risk classes I or II generally are candidates for outpatient treatment, risk class III patients are potential candidates for outpatient treatment or brief inpatient observation, and patients in classes IV and V should be hospitalized (table 4). Estimates from the Pneumonia PORT cohort study suggest that these recommendations would reduce the proportion of patients receiving traditional inpatient care by 31% and that there would be a brief observational inpatient stay for an additional 19%. Table 4 Risk-class mortality rates. The effectiveness and safety of applying the Pneumonia PORT prediction rule to the initial site of care for an independent population of patients with CAP have been examined with use of a modified version of the Pneumonia PORT prediction rule [36]. Emergency room physicians were educated about the rule and were encouraged to treat those in risk classes I–III as outpatients, with close, structured follow-up and provision of oral clarithromycin at no cost to the patient, if desired. The outcomes for those treated at home during this intervention phase were compared with the outcomes for historical control subjects from the time period immediately preceding the intervention. During the intervention period, there were 166 eligible patients classified as “low risk” for short-term mortality (risk classes I–III) for comparison with 147 control subjects. The percentage treated initially as outpatients was higher during the intervention period than during the control period (57% vs. 42%; relative increase of 36%; P=.01). When initial plus subsequent hospitalization was used as the outcome measure, there was a trend toward more outpatient care during the intervention period, but the difference was no longer statistically significant (52% vs. 42%; P=.07). None of those initially treated in the outpatient setting during the intervention period died within 4 weeks of presentation. A second multicenter controlled trial subsequently assessed the effectiveness and safety of using the Pneumonia PORT prediction rule for the initial site-of-treatment decision [37]. In this trial, 19 emergency departments were randomly assigned either to continue conventional management of CAP or to implement a critical pathway that included the Pneumonia PORT prediction rule to guide the admission decision. Emergency room physicians were educated about the rule and were encouraged to treat those in risk classes I–III as outpatients with oral levo-floxacin. Overall, 1743 patients with CAP were enrolled in this 6-month study. Use of the prediction rule resulted in an 18% reduction in the admission of low-risk patients (31% vs. 49%; P=.013). Use of the rule did not result in an increase in mortality or morbidity and did not compromise patients' 30-day functional status. These studies support use of the Pneumonia PORT prediction rule to help physicians identify low-risk patients who can be safely treated in the outpatient setting. The IDSA panel endorses the findings of the Pneumonia PORT prediction rule, which identifies valid predictors for mortality and provides a rational foundation for the decision regarding hospitalization. However, it should be emphasized that the PORT prediction rule is validated as a mortality prediction model and not as a method to triage patients with CAP. New studies are required to test the basic premise underlying the use of this rule in the initial site-of-treatment decision, so that patients classified as “low risk” and treated in the outpatient setting will have outcomes equivalent to or better than those of similar “low-risk” patients who are hospitalized. It is important to note that prediction rules are meant to contribute to rather than to supersede physicians' judgment. Another limitation is that factors other than severity of illness must also be considered in determining whether an individual patient is a candidate for outpatient care. Patients designated as “low risk” may have important medical and psychosocial contraindications to outpatient care, including expected compliance problems with medical treatment or poor social support at home. Ability to maintain oral intake, history of substance abuse, cognitive impairment, and ability to perform activities of daily living must be considered. In addition, patients may have rare conditions, such as severe neuromuscular disease or immunosuppression, which are not included as predictors in these prediction rules but increase the likelihood of a poor prognosis. Prediction rules may also oversimplify the way physicians interpret important predictor variables. For example, extreme alterations in any one variable have the same effect on risk stratification as lesser changes, despite obvious differences in clinical import (e.g., a systolic blood pressure of 40 mm Hg vs. one of 88 mm Hg). Furthermore, such rules discount the cumulative importance of multiple simultaneous physiological derangements, especially if each derangement alone does not reach the threshold that defines an abnormal value (e.g., systolic blood pressure of 90/40 mm Hg, respiratory rate of 28 breaths/min, and pulse of 120 beats/min). Finally, prediction rules often neglect the importance of patients' preferences in clinical decision-making. This point is highlighted by the observation that the vast majority of low-risk patients with CAP do not have their preferences for site of care solicited, despite strong preferences for outpatient care [38]. Role of Specific Pathogens in CAP Prospective studies evaluating the causes of CAP in adults have failed to identify the cause of 40%–60% of cases of CAP and have detected ≥2 etiologies in 2%–5% [2, 7, 26, 39, 40]. The most common etiologic agent identified in virtually all studies of CAP is S. pneumoniae, which accounts for about two-thirds of all cases of bacteremic pneumonia cases [9]. Other pathogens implicated less frequently include H. influenzae (most strains of which are nontypeable), Mycoplasma pneumoniae, C. pneumoniae, S. aureus, Streptococcus pyogenes, N. meningitidis, Moraxella catarrhalis, Klebsiella pneumoniae and other gram-negative rods, Legionella species, influenza virus (depending on the season), respiratory syncytial virus, adenovirus, parainflu-enza virus, and other microbes. The frequency of other etiologies is dependent on specific epidemiological factors, as with Chlamydia psittaci (psittacosis), Coxiella burnetii (Q fever), Francisella tularensis (tularemia), and endemic fungi (histoplasmosis, blastomycosis, and coccidioidomycosis). Comparisons of relative frequency of each of the etiologies of pneumonia are hampered by the varying levels of sensitivity and specificity of the tests used for each of the pathogens that they detect; for example, in some studies, tests used for legionella infections provide a much higher degree of sensitivity and possibly specificity than do tests used for pneumococcal infections. Thus, the relative contribution of many causes to the incidence of CAP is undoubtedly either exaggerated or underestimated, depending on the sensitivity and specificity of tests used in each of the studies. Etiology-Specific Diagnoses and the Clinical Setting No convincing association has been demonstrated between individual symptoms, physical findings, or laboratory test results and specific etiology [39]. Even time-honored beliefs, such as the absence of productive cough or inflammatory sputum in pneumonia due to Mycoplasma, Legionella, or Chlamydia species, have not withstood close inspection. On the other hand, most comparisons have involved relatively small numbers of patients and have not evaluated the potential for separating causes by use of constellations of symptoms and physical findings. In one study, as yet unconfirmed, that compared patients identified in a prospective standardized fashion, a scoring system using 5 symptoms and laboratory abnormalities was able to differentiate most patients with legionnaires' disease from the other patients [41]. A similar type of system has been devised for identifying patients with hantavirus pulmonary syndrome (HPS) [42]. If validated, such scoring systems may be useful for identifying patients who should undergo specific diagnostic tests (which are too expensive to use routinely for all patients with CAP) and be empirically treated with specific antimicrobial drugs while test results are pending. Certain pathogens cause pneumonia more commonly among persons with specific risk factors. For instance, pneumococcal pneumonia is especially likely to occur in the elderly and in patients with a variety of medical conditions, including alcoholism, chronic cardiovascular disease, chronic obstructed airway disease, immunoglobulin deficiency, hematologic malignancy, and HIV infection. However, outbreaks occur among young adults under conditions of crowding, such as in army camps or prisons. S. pneumoniae is second only to Pneumocystis carinii as the most common identifiable cause of acute pneumonia in patients with AIDS [43–45]. Legionella is an opportunistic pathogen; legionella pneumonia is rarely recognized in healthy young children and young adults. It is an important cause of pneumonia in organ transplant recipients and in patients with renal failure and occurs with increased frequency in patients with chronic lung disease, smokers, and possibly those with AIDS [46]. Although M. pneumoniae historically has been thought primarily to involve children and young adults, some evidence suggests that it causes pneumonia in healthy adults of any age [8]. There are seasonal differences in incidence of many of the causes of CAP. Pneumonia due to S. pneumoniae, H. influenzae, and influenza occurs predominantly in winter months, whereas C. pneumoniae appears to cause pneumonia year-round. Although there is a summer prevalence of outbreaks of legionnaires' disease, sporadic cases occur with similar frequency during all seasons [8, 46]. Some studies suggest that there is no seasonal variation in mycoplasma infection; however, other data suggest that its incidence is greatest during the fall and winter months [47]. There are other temporal variations in incidence of some causes of pneumonia. The frequency and severity of influenza vary as a result of antigenic drift and, occasionally, as a result of antigenic shift. For less clear reasons, increases in incidence of mycoplasma infections occur every 3–6 years [47, 48]. Year-to-year variations may also occur with pneumococcal pneumonia [49]. Little is known about geographic differences in the incidence of pneumonia. Surveillance data from the CDC suggest that legionnaires' disease occurs with highest incidence in northeastern states and states in the Great Lakes area [46]; however, differences in ascertainment of disease may be a contributing factor. The incidence of pneumonia due to pathogens that are environmentally related would be expected to vary with changes in relevant environmental conditions. For example, the incidence of legionnaires' disease is dependent on the presence of pathogenic Legionella species in water, amplification of the bacteria in reservoirs with the ideal nutritional milieu, use of aerosol-producing devices (which can spread contaminated water via aerosol droplets), ideal meteorological conditions for transporting aerosols to susceptible hosts, and presence of susceptible hosts. Alterations in any of these variables would probably lead to variations in incidence. Likewise, increasing rainfall, with associated increases in the rodent population, was hypothesized to be the basis for the epidemic of HPS in the southwestern United States in 1993 [50]. Diagnostic Evaluation Pneumonia should be suspected in patients with newly acquired lower respiratory symptoms (cough, sputum production, and/or dyspnea), especially if accompanied by fever, altered breath sounds, and rales. It is recognized that there must be a balance between reasonable diagnostic testing (table 5) and empirical therapy. The importance of establishing the diagnosis of pneumonia and its cause is heightened with the increasing concern about antibiotic overuse. Table 5 Diagnostic studies for evaluation of community-acquired pneumonia. Chest Radiography The diagnosis of CAP is based on a combination of clinical and laboratory (including microbiological) data. The differential diagnosis of lower respiratory symptoms is extensive and includes upper and lower respiratory tract infections, as well as noninfectious causes (e.g., reactive airways disease, atelectasis, congestive heart failure, bronchiolitis obliterans with organizing pneumonia [BOOP], vasculitis, pulmonary embolism, and pulmonary malignancy). Most cases of upper respiratory tract infection and AB are of viral origin, do not require anti-microbial therapy, and are the source of great antibiotic abuse [51, 52]. By contrast, antimicrobial therapy is usually indicated for pneumonia, and a chest radiography is usually necessary to establish the diagnosis of pneumonia. Physical examination to detect rales or bronchial breath sounds is neither sensitive nor specific for detecting pneumonia [53]. Chest radiography is considered sensitive and, occasionally, is useful for determining the etiologic diagnosis, the prognosis, and alternative diagnoses or associated conditions. Chest radiographs in patients with P. carinii pneumonia (PCP) are false-negative for up to 30% of patients, but this exception is not relevant for the immunocompetent adult host [54]. One study showed spiral CT scans are significantly more sensitive in detecting pulmonary infiltrates [55], but the clinical significance of these results is unclear, and the IDSA panel does not endorse the routine use of this technology because of the preliminary nature of the data and high cost of the procedure. At times of limited resources, it may seem attractive to treat patients for CAP on the basis of presenting manifestations, without radiographic confirmation. This approach should be discouraged, given the cost and potential dangers of antimicrobial abuse in terms of side effects and resistance. Indeed, the prevalence of pneumonia among adults with respiratory symptoms that suggest pneumonitis ranges from only 3% in a general outpatient setting to 28% in an emergency department [56, 57]. The IDSA panel recommends that chest radiography be included in the routine evaluation of patients for whom pneumonia is considered a likely diagnosis (A-II). Etiology The emphasis on microbiological studies (Gram staining and culture of expectorated sputum) in the IDSA guidelines represents a difference from the guidelines of the American Thoracic Society [1]. Arguments against microbiological studies include the low yield in many reports and the lack of documented benefit in terms of cost or outcome. A concern of the IDSA panel members is our perception that the quality of microbiological technology, as applied to respiratory secretions, has deteriorated substantially, compared with that in an earlier era [12]. Furthermore, it is our perception that regulations of the Clinical Laboratory Improvement Act, which discourage physicians from examining sputum samples microscopically, contributed to this decline. Although no data clearly demonstrate the cost-effectiveness or other advantages of attempts to identify pathogens, studies specifically designed to address this issue have not been reported. Our rationale for the preservation of microbiological and immunologic testing is summarized in table 6, which classifies advantages with regard to the individual patient, society, and costs. The desire to identify the etiologic agent is heightened by concern about empirical selection of drugs, because of the increasing microbial resistance, unnecessary costs, and avoidable side effects. In addition, the work of prior investigators and their microbiological findings provide the rationale considered essential to the creation of guidelines based on probable etiologic agents. Table 6 Rationale for establishing an etiologic diagnosis. A detailed history may be helpful for suggesting a diagnosis. Epidemiological clues that may lead to diagnostic considerations are listed in table 7. Certain findings have historically been identified as clues to specific causes of pneumonia, although these have not been confined to controlled studies. Acute onset, a single episode of shaking with chills (rigor), and pleurisy suggest pneumococcal infection. Prodromal fever and myalgia followed by pulmonary edema and hypotension are characteristic of HPS. Underlying COPD is more often seen with pneumonia due to H. influenzae or M. catarrhalis, separately or together with S. pneumoniae. Putrid sputum indicates infection caused by anaerobic bacteria. Although many studies of CAP have found that clinical features often do not distinguish etiologic agents [39, 58, 59], others support the utility of clinical clues for supporting an etiologic diagnosis [41, 60]. Table 7 Epidemiological conditions related to specific pathogens in patients with selected community-acquired pneumonia. Once the clinical diagnosis of CAP has been made, consideration should be given to microbiological diagnosis with bacteriologic studies of sputum and blood [61–66]. Practice standards for collection, transport, and processing of respiratory secretions to detect common bacterial pathogens are summarized in table 8. Many pathogens require specialized tests for their detection, which are summarized in table 9. The rapid diagnostic test for routine use is Gram staining of respiratory secretions, usually expectorated sputum; others include direct fluorescent antibody (DFA) staining of sputum or urinary antigen assay for Legionella, for use in selected cases, urinary antigen assay for S. pneumoniae, acid-fast bacilli (AFB) staining for detection of mycobacterial infections, and several tests for influenza. Table 8 Recommendations for expectorated sputum collection, transport, and processing. Table 9 Diagnostic studies for specific agents of community-acquired pneumonia. Many rapid diagnostic tests, such as PCR, are in early development, not commonly available, or not sufficiently reliable [66]. PCR testing for detection of Mycobacterium tuberculosis is the only PCR test for detection of a respiratory tract pathogen that has been cleared by the US Food and Drug Administration (FDA), but it is recommended for use only with specimens that contain AFB on direct smears. Diagnostic procedures that provide identification of a specific etiology within 24–72 h can still be useful for guiding continued therapy. The etiologic diagnosis can be useful for both prognostic and therapeutic purposes. Once a diagnosis has been established, the failure to respond to treatment can be dealt with in a logical fashion based on the causative organism and its documented antibiotic susceptibility, rather than by empiric selection of antimicrobial agents with a broader or different spectrum. Furthermore, if a drug reaction develops, an appropriate substitute can be readily selected. Performance of blood cultures within 24 h of admission for CAP is associated with a significant reduction in 30-day mortality [67]. With regard to sputum bacteriology, several studies have suggested that mortality associated with CAP in hospitalized patients is the same for those with and without an etiologic diagnosis [68–70]. These studies were not specifically designed to test the hypothesis. Instead, the conclusion is based on retrospective analyses of cases with and without an etiologic diagnosis. Other outcomes also of interest that have not been assessed are length of stay, cost, resource use, and morbidity. Some studies, although uncontrolled, do suggest benefit of these diagnostic studies [71–76]. For example, Boerner and Zwadyk [64] reported that a positive early diagnosis by sputum Gram staining correlated with more rapid resolution of fever after initiation of antimicrobial therapy. An additional study by Torres et al. [76] showed that inadequate antibiotic treatment was clearly related to poor outcomes, which suggests that the establishment of an etiologic diagnosis is important. The frequency of microbiological studies for CAP patients is highly variable. A report from the Pneumonia PORT study, with analysis of 1343 hospitalized patients during 1991–1994, showed that the frequencies of sputum Gram staining and sputum culture within 48 h of admission were 53% and 58%, respectively [77]. These studies were done on only 8%–11% of 944 outpatients with CAP. Participating centers in this and most other published studies of CAP are academic institutions at which microbiological studies are probably more frequent than in other health care settings. The finding of a likely pathogen in blood cultures averages 11% in published reports concerning hospitalized patients with CAP [9]. The yield with sputum studies is highly variable, ranging from 29% to 90% for hospitalized patients and usually 25 PMN+ 10 WBC per SEC. Mycobacteria and Legionella species are exceptions, since microscopic criteria may yield misleading results. Cultures should be performed rapidly [83], although the consequence of time delays in processing is disputed [84]. Interpretations of expectorated sputum cultures should include clinical correlations and semiquantitative results. In office practice, it may not be realistic to perform Gram staining in a timely manner to guide antibiotic decisions, but a slide may be prepared, air-dried, and heat-fixed for subsequent interpretation (C-III). Numerous studies support the use of routine microscopic examination of a gram-stained sputum sample, with recognition of lancet-shaped gram-positive diplococci that suggest S. pneumoniae. Most show the sensitivity of sputum Gram staining for patients with pneumococcal pneumonia to be 50%–60% and the specificity to be >80% [60, 63–65, 75]. In a prospective study of 144 patients admitted to the hospital with CAP, 59 (41%) had a valid specimen obtained, with the cytological criteria of >25 PMN and 90% of patients on the basis of gram-staining results [75]. In haemophilus pneumonia, the Gram stain reading is even more reliable because of the profuse number of organisms that are regularly present. The finding of many WBC with no bacteria in a patient who has not already received antibiotics can reliably exclude infection by most ordinary bacterial pathogens. The validity of the gram-stain reading, however, is directly related to the experience of the interpreter [85]. Routine cultures of expectorated sputum are neither sensitive nor specific when the common bacteriologic methods of many laboratories are used. The most likely explanation for unreliable microbiological data is that the specimen did not provide a rich enough source of inflammatory material from the lower respiratory tract, either because the patient was unable to cough up a reliable specimen or because the health care provider did not give sufficient priority to obtaining such a specimen. Other reasons include prior administration of antibiotics, delays in processing the specimen, insufficient attention to separating sputum from saliva before streaking slides or culture plates, and difficulty with interpretation because of the contamination by the flora of the upper airways. The flora may include potential pathogens (leading to false-positive cultures), and the normal flora often overgrow the true pathogen (leading to false-negative cultures), especially with fastidious pathogens such as S. pneumoniae. In cases of bacteremic pneumococcal pneumonia, S. pneumoniae may be isolated in sputum culture in only 40%–50% of cases when standard microbio-logical techniques are used [86, 87]. The yield of S. pneumoniae is substantially higher from transtracheal aspirates [88–91], transthoracic needle aspirates [89, 92], and quantitative cultures of BAL aspirates [89, 93]. Prior antibiotic therapy may reduce the yield of common respiratory pathogens in cultures of respiratory tract specimens from any source and is often associated with false-positive cultures for upper airway contaminants, such as gram-negative bacilli or S. aureus [62, 89]. 3. Induced sputum: the utility of these specimens for detecting pulmonary pathogens other than P. carinii or M. tuberculosis is poorly established. 4. Serological studies: these tests are usually not helpful in the initial evaluation of patients with CAP (C-III) but may provide data useful for epidemiological surveillance. Cold agglutinins in a titer ≥1:64 support the diagnosis of M. pneumoniae infection, with a sensitivity of 30%–60%, but this test has poor specificity. IgM antibodies to M. pneumoniae require up to 1 week to reach diagnostic titers; reported results for sensitivity are variable [94, 95]. The serological responses to Chlamydia and Legionella species take even longer [96, 97]. The acute antibody test for Legionella in legionnaires' disease is usually negative or demonstrates a low titer [98, 99]. Some authorities have accepted an acute titer ≥1:256 as a criterion for a probable or presumptive diagnosis, but 1 study showed that this titer had a positive predictive value of only 15% [99]. If serological tests are to be used, an acute-phase serum specimen must be obtained from selected patients. Then, if the etiology of a case remains in question, a convalescent-phase serum can be obtained, and serological studies of paired sera can be performed. This method to identify causative agents is primarily for epidemiological information. These data indicate that there are no commonly available serological tests that can be used to accurately guide therapy for acute infections caused by M. pneumoniae, C. pneumoniae, or Legionella (D-III). 5. Antigen detection: antigen-detection methods for identification of microorganisms in sputum and in other fluids have been studied for >70 years with a variety of techniques—counter-immunoelectrophoresis, latex agglutination, immunofluorescence, and enzyme immunoassay (EIA). Although their use for identification of bacterial agents (i.e., S. pneumoniae) has been favored in many European centers, they have been less acceptable to North American laboratories. Cost, time requirements, and relative lack of sensitivity and specificity (depending on the method) are potential limitations. The FDA has recently approved an immunochromatographic membrane assay to detect S. pneumoniae antigen in urine. Results may be obtained as quickly as 15 min after initi-ation of the test. According to the package insert, the test has a sensitivity of 86% and a specificity of 94%. Disadvantages are the limited experience with the assay, the need for cultures in order to determine susceptibility to guide therapy, and the lack of published data on performance characteristics. The IDSA panel endorses this test as a complement to sputum and blood cultures (C-III). The Quellung test also is a rapid assay to detect S. pneumoniae but requires adequate expertise. Rapid, commercially available EIAs are available for detection of respiratory syncytial virus (RSV), adenovirus, and parainfluenza viruses 1, 2, and 3. The sensitivities of these tests are >80%. Rapid methods to detect influenza virus are of special interest because of the availability of antiviral agents that must be given within 48 h of the onset of symptoms. These tests show sensitivities of 70%–85% and a specificity >90%. Clinical detection of influenza on the basis of typical symptoms during an influenza epidemic appears more sensitive [100]. The urinary antigen tests have been shown to be sensitive and specific for detection of L. pneumophila serogroup 1, which accounts for ∼70% of reported legionella cases in the United States [46, 98]; other possible advantages are the technical ease with which the test is performed and the validity of results after several days of effective antibiotic treatment. DFA staining of respiratory secretions is technically demanding, shows optimal results with L. pneumophila, and shows poor sensitivity and specificity when not performed by experts using only certain antibodies. Culture and urine antigen testing show sensitivity of 50%–60% and a specificity of >95%. A negative laboratory test does not exclude Legionella, particularly if the case is caused by organisms other than L. pneumophila serogroup 1, but a positive culture or urine antigen assay is virtually diagnostic. The IDSA panel recommends urinary antigen assays and sputum culture on selective and nonselective media, with specimen decontamination before plating, to detect legionnaires' disease (A-II). 6. DNA probes and amplification: several rapid diagnostic tests that use nucleic acid amplification for the evaluation of respiratory secretions or serum are presently under development, especially for Chlamydia, Mycoplasma, and Legionella [66]. The reagents for these tests have not been cleared by the FDA, and their availability is generally restricted to research and reference laboratories [66, 96]. If such tests become available, they may be helpful in establishing early diagnosis and allowing for directed therapy at the time of care. Their greatest potential utility is anticipated for the detection of M. pneumoniae, Legionella, and selected pathogens that infrequently colonize the upper airways in the absence of disease (table 9). 7. Invasive diagnostic tests (transtracheal aspiration, bronchoscopy, and percutaneous lung aspiration; table 3): transtracheal aspiration was previously used to obtain uncontaminated lower respiratory secretions that were valid for culture for the detection of anaerobic organisms, as well as common aerobic pathogens [62, 89]. This procedure is now infrequently performed because of concern about adverse effects and the lack of personnel skilled in the technique. A consequence of reduced use of transtracheal aspiration is the lack of any method to detect anaerobic bacteria in the lung in the absence of empyema or bacteremia. The utility of fiber-optic bronchoscopy is variable, depending on pathogen and technique. Because aspirates from the inner channel of the bronchoscope are subject to contamination by the upper airway flora, they should not be cultured anaerobically, since they have the same limitations as expectorated sputum [89, 101]. For recovery of common bacterial pathogens, quantitative culture of BAL or of a protected-brush catheter specimen is considered superior [102, 103]. The techniques for collection, transport, and processing of specimens for quantitative culture are available from published sources [89, 102, 103]. Bronchoscopy is impractical for routine use, because it is expensive, requires technical expertise, and may be difficult to perform in a timely manner. Some authorities favor its use in patients with a fulminant course, who require admission to an ICU, or have complex pneumonia unresponsive to antimicrobial therapy [89, 93, 104, 105]. Bronchoscopy is especially useful for the detection of selected pathogens, such as P. carinii, Mycobacterium species, and cytomegalovirus [89]. The IDSA panel recommends blood cultures and expectorated sputum Gram staining and culture as the only microbio-logical studies to be considered routine for patients hospitalized with CAP. Transtracheal aspiration, transthoracic needle aspiration, and bronchoscopy should be reserved for selected patients and then used only with appropriate expertise (B-III). With regard to recommendations about diagnostic approach, table 5 lists diagnostic studies recommended for hospitalized patients, according to severity of illness (B-II). Special Considerations Pneumococcal Pneumonia S. pneumoniae is among the leading infectious causes of illness and death worldwide for young children, persons who have underlying chronic systemic conditions, and the elderly. A meta-analysis of 122 reports of CAP in the English-language literature from 1966 through 1995 showed that S. pneumoniae accounted for two-thirds of >7000 cases in which an etiologic diagnosis was made, as well as for two-thirds of the cases of lethal pneumonia [9]. In the United States, it is estimated that 125,000 cases of pneumococcal pneumonia necessitate hospitalization each year. A vaccine for the most common serotypes of S. pneumoniae is available, and the Advisory Committee on Immunization Practices recommends that the vaccine be administered to all persons aged ≥65 years and younger patients who have underlying medical conditions associated with increased risk for pneumococcal disease and its complications [106]. Revaccination is recommended after 5–7 years. Until recently in the United States, S. pneumoniae was nearly uniformly susceptible to penicillin, which allowed clinicians to treat patients with severe pneumococcal infection with penicillin G alone or nearly any other commonly used antibiotic, without testing for drug susceptibility. Resistance of S. pneumoniae to penicillin and to other antimicrobial drugs, first noted in Australia and Papua New Guinea in the 1960s, was found to be a major problem in South Africa in the 1970s and, subsequently, in many countries in Europe, Africa, and Asia in the 1980s. In the United States, nonsusceptibility to penicillin has increased markedly during the last decade [107–109] and appears to be continuing [110–112]. The susceptibility of S. pneumoniae to penicillin is currently defined by the National Committee for Clinical Laboratory Standards (NCCLS) as follows. Susceptible isolates are inhibited by 0.06 µg/mL (i.e., the MIC is ≤0.06 µg/mL). Isolates with reduced susceptibility (also known as intermediate resistance) are inhibited by 0.1–1.0 µg/mL, and resistant isolates by ≥2.0 µg/mL. Amoxicillin is more effective than penicillin against pneumococci in vitro, with MIC thresholds that are higher. An important problem with these definitions is that, from a clinical point of view, the MIC has entirely different meaning, depending on the infection being treated. A strain with reduced susceptibility (e.g., MIC, 0.5 µg/mL) behaves as a susceptible organism when it causes pneumonia (see below) but probably not when it causes meningitis [111, 113]. On the basis of present definitions and depending on the source of the isolates, as of June 1999 in the United States, ∼25%–35% of S. pneumoniae isolates from infected persons were intermediately resistant or resistant to penicillin [110–112]. Variations occur from city to city and within segments of the population or even within institutions in a single city, so the actual results vary greatly, depending on the source of the isolates. NCCLS definitions are based on levels achieved in CSF in cases of meningitis. Much higher levels are achieved in blood and in alveoli. For these reasons, in treating pneumonia with generally accepted doses of penicillins, intermediate resistance is not clinically important; resistance may be important, especially if it is high-grade (e.g., MIC, >4 µg/mL). Rates of resistance are substantially higher in many European countries than in the United States, with notable exceptions, such as the Netherlands and Germany; in these countries, accepted standards of practice strictly limit antibiotic usage, especially among very young children. Resistance to penicillin is only one small part of the picture. Although the majority of strains with reduced susceptibility to penicillin are susceptible to certain third-generation cephalosporins, such as cefotaxime or ceftriaxone (defined by an MIC ≤0.5 µg/mL), intermediate resistance to these drugs (MIC, 1.0 µg/mL), and resistance (MIC, >2.0 µg/mL) are increasing [111]. In accordance with these definitions, up to one-half of strains with reduced penicillin susceptibility also have reduced susceptibility to these cephalosporins (table 11). A greater proportion exhibit resistance to other third-generation and to second-generation cephalosporins. As is the case for penicillin, pneumonia caused by intermediately resistant or even some resistant isolates is likely to respond to treatment with standard doses of cefotaxime or ceftriaxone. Cefuroxime is less active against S. pneumoniae, and the activity of this or other cephalosporins cannot be predicted by results of in vitro susceptibility tests with cefotaxime or ceftriaxone. Table 11 Susceptibility of Streptococcus pneumoniae to commonly used antimicrobial agents, stratified by susceptibility to penicillin. Most important, resistance extends far beyond the β-lactam antibiotics. Although the genetics of pneumococcal resistance is complex, β-lactam-resistant organisms often have acquired genes that confer resistance to other classes of antimicrobials through transformation or conjugative transposons. Thus, pneumococci that are penicillin-resistant are also often resistant to other antibiotics, and the most appropriate term to characterize them is multiply antibiotic-resistant (table 11; these data reflect the general situation in the United States as of October 1999). Resistance to some of these antimicrobials can be overcome by increasing the dose of antibiotic. Macrolides are an example. In the United States, most macrolide resistance is a result of increased drug efflux encoded by mefE (erythromycin MIC, 2–32 µg/mL, and susceptible to clindamycin); it is possible that this resistance may be overcome by achievable levels of macrolides [114]. In Europe, most macrolide resistance is due to a ribosomal methylase encoded by ermAM; this results in high-grade resistance to macrolides and resistance to clindamycin that probably cannot be overcome. It is important to emphasize that resistance to newer macrolides, such as azithromycin or clarithromycin, parallels resistance to erythromycin. The prevalence of resistance to tetracyclines among pneumococci is similar to that of resistance to macrolides, but resistance to trimethoprim-sulfamethoxazole (TMP-SMZ) is far more prevalent, and use of this combination is discouraged [109–112]. Among FDA-approved drugs, only vancomycin and linezolid are currently effective against essentially all pneumococci. Fluoroquinolones are active against >98% of strains, including penicillin-resistant strains, but resistance to these drugs has begun to increase in some areas where they are used extensively [115–118]. Of the newer drugs, the oxazolidinones [119] and glycopeptides [120] appear to be most promising, with MICs for drug-resistant S. pneumoniae being no higher than those for penicillin-susceptible strains. Resistance to the streptogramins appears to parallel that to the macrolides. Studies of oral outpatient therapy for pneumonia, in which the majority of cases have probably been due to S. pneumoniae, have shown a good outcome, regardless what therapy is given; however, these studies were not designed to examine antibiotic resistance among pneumococci. Recommended antimicrobial agents for empirical treatment of pneumococcal pneumonia include amoxicillin (500 mg thrice daily), cefuroxime axetil (500 mg twice daily), cefpodoxime (200 mg twice daily), cefprozil (500 mg twice daily), and azithromycin, clarithromycin, erythromycin, or a quinolone or doxycycline in ordinarily prescribed dosages. Amoxicillin is preferred to penicillin because of more reliable absorption, longer half-life, and slightly more favorable MICs. Although recent surveillance studies indicate increasing resistance to macrolides, to date there is a paucity of reports of clinical failure in patients without risk factors for infection with drug-resistant S. pneumoniae [114]. With increasing use, however, there is concern about reduced efficacy of macrolides. In hospitalized patients, pneumococcal pneumonia caused by organisms that are susceptible or intermediately resistant to penicillin responds to treatment with penicillin (2 million units every 4 h), ampicillin (1 g every 6 h), cefotaxime (1 g every 8 h), or ceftriaxone (1 g every 24 h). Pneumonia due to penicillin- or cephalosporin-resistant organisms probably requires higher doses of these drugs. Retrospective studies [121, 122] have shown a similar outcome after treatment with standard doses of a penicillin or a cephalosporin, without regard to whether pneumonia was due to susceptible or nonsusceptible organisms, but the number of subjects infected with resistant pneumococci (MIC, ≥2 µg/mL) was very small, and there was a trend toward worse outcomes in both studies [121, 122]. A CDC study found mortality associated with treated pneumococcal pneumonia to be increased 3-fold when the condition was due to penicillin-resistant pneumococci and 7-fold when due to ceftriaxone-resistant pneumococci, even after adjusting for severity of underlying illness and previous hospitalization, both of which increase the likelihood that resistant pneumococci will be present [123]. This study, however, did not determine the nature of the treatment in each case. It seems likely that, ultimately, penicillin or ceftriaxone may not reliably cure infection caused by strains of S. pneumoniae for which penicillin MICs are ≥4 µg/mL and ceftriaxone MICs are ≥8 µg/mL. At present, many authorities treat pneumococcal pneumonia, even in critically ill patients, with cefotaxime (1 g every 6–8 h) or ceftriaxone (1 g every 12–24 h). Many patients have received 1–2 g of ampicillin (with or without sulbactam) every 6 h, with a good response. Although vancomycin is nearly certain to provide antibiotic coverage, there is a strong impetus not to use this drug until it is proven to be needed because of fear of the emergence of resistant organisms. Vancomycin or a fluoroquinolone should be used for initial treatment of pneumococcal pneumonia in critically ill patients who are allergic to β-lactam antibiotics. Quinupristin/dalfopristin or linezolid are other options, but experience with these antimicrobial agents for pneumococcal pneumonia is extremely limited. Aspiration Pneumonia Aspiration pneumonia is broadly defined as the pulmonary sequela of abnormal entry of material from the stomach or upper respiratory tract into the lower airways. The term generally applies to large-volume aspiration. There are at least 3 distinctive forms [124], based on the nature of the inoculum, the clinical presentation, and management guidelines: toxic injury of the lung (such as due to gastric acid aspiration or Mendelson's syndrome), obstruction (with a foreign body or fluids), or infection (table 12). These syndromes are reviewed elsewhere [125, 126]. Most studies show that aspiration is suspected in 5%–10% of patients hospitalized with CAP, although the criteria for this diagnosis are often not provided. In general, the diagnosis should be suspected when patients have a condition that predisposes them to aspiration (usually compromised consciousness or dysphagia) and radiographic evidence of involvement of a dependent pulmonary segment (lower lobes are dependent in the upright position; the superior segments of the lower lobes and posterior segments of the upper lobes are dependent in the recumbent position). Table 12 Characteristics of the various forms of aspiration pneumonia. Aspiration pneumonia is the presumed cause of nearly all cases of anaerobic pulmonary infection, and microaerophiles and anaerobes from the mouth flora are the anticipated patho-gens in bacterial infections associated with aspiration. Anaerobic Bacterial Infections The frequency of infection that involves anaerobes among patients with CAP is not known, because the methods required to obtain uncontaminated specimens that are valid for anaerobic culture are rarely used. The usual specimens are transtracheal aspirates, pleural fluid, transthoracic needle aspirates, and uncontaminated specimens from metastatic sites [89, 127, 128]; a limited experience suggests that quantitative cultures of protected-brush or BAL specimens collected at bronchoscopy may be acceptable [89, 102, 103, 127]. Anaerobic and microaerophilic bacteria are the most common etiologic agents of lung abscess and aspiration pneumonia and are relatively common isolates in empyema [126]. Characteristically, many bacterial species are isolated from infected tissues. Patients with anaerobic bacterial infection may also present with pneumonitis that is indistinguishable from other common forms of bacterial pneumonia on the basis of clinical features [129]. Clinical clues to this diagnosis include a predisposition to aspiration, infection of the gingival crevice (gingivitis), putrid discharge, necrosis of tissue with abscess formation or a bronchopulmonary fistula, infection complicating airway obstruction, chronic course, and infection in a dependent pulmonary segment [126]. Anaerobes may also account for a substantial number of cases of CAP that do not have these characteristic features [102, 126, 130]. With regard to therapy, the only comparative therapeutic trials for anaerobic lung infections have been with lung abscess, and these show clindamycin to be superior to iv penicillin [130, 131]. Using metronidazole alsone as antimicrobial therapy is associated with a high failure rate, presumably because of the role played by facultative and microaerophilic streptococci. Amoxicillin-clavulanate (A-I) also appears to be effective [132]. Antibiotics that are virtually always active against anaerobes in vitro include imipenem, meropenem, metronidazole, chloramphenicol, and any combination of a β-lactam / β-lactamase inhibitor. Moxifloxacin, gatifloxacin, and trovafloxacin also have good in vitro activity against most anaerobes. Macrolides, cephalosporins, and doxycycline have variable activity. TMP-SMZ and aminoglycosides are not active against most anaerobes. The IDSA panel recommends clindamycin, a β-lactam / β-lactamase inhibitor, imipenem, and meropenem as preferred drugs for treating pulmonary infections when anaerobic bacteria are established or suspected as the cause (B-I). C. pneumoniae Pneumonia Although prevalence varies from year to year and within geographic settings, C. pneumoniae causes ∼5%–15% of cases of CAP [8, 39, 40, 133–135]; the majority of cases of pneumonia are relatively mild and associated with low mortality [133, 134]. C. pneumoniae pneumonia may present with sore throat, hoarseness, and headache as important nonpneumonic symptoms; other findings include sinusitis, reactive airways disease, and empyema. Reinfection is common, and hospitalization due to pneumonia caused by C. pneumoniae usually occurs for older patients who have reinfection, in which comorbidities undoubtedly play a significant role in the clinical course. When C. pneumoniae is found in association with other pathogens, particularly S. pneumoniae, the associated pathogen appears to determine the clinical course of the pneumonia [133]. Infection can be suspected with culture of C. pneumoniae, DNA detection and PCR, and serology (most specifically by microimmuno-fluo-res-cent antibodies) [66, 96, 133–135]. However, cell culture is not routinely available except in research laboratories; in addition, PCR technology is not standardized, reagents for PCR are not FDA cleared, and serology is problematic because of nonspecificity [66, 136]. The preferred diagnostic finding is documentation of a 4-fold increase in titer from acute to convalescent specimens, with supporting evidence by PCR or culture. Accordingly, most laboratories cannot confirm a diagnosis of C. pneumoniae pneumonia in a timely fashion, so treatment must be empirical (A-II). For therapy, the IDSA panel recommends a macrolide, doxycycline, or a fluoroquinolone (B-II) [134, 137]. Legionnaires' Disease Legionella is implicated in 2%–6% of CAP cases in most hospital-based series; some groups report higher rates that presumably reflect local epidemiology and/or more sensitive laboratory techniques [8, 39–41, 138]. Risk is related to exposure, increasing age, smoking, and compromised cell-mediated immunity such as in transplant recipients [46]. Although rare in immunocompetent adults aged 700 units/mL, or severe disease [138]. Methods of laboratory detection include culture, serology, DFA staining, urinary antigen assay, and PCR. DFA stains require substantial expertise for interpretation, and selection of reagents is critical. PCR is expensive, and there are no FDA-cleared reagents. Tests recommended by the IDSA panel are urinary antigen assay for L. pneumophila serogroup 1, which is not technically demanding and reliably and rapidly detects up to 70% of cases of legionnaires' disease, and culture on selective media, which detects all strains but is technically demanding [46, 139] (B-II). Historically, the preferred therapeutic agent has been erythromycin, usually in a total daily dose of 2–4 g iv, with or without rifampin (600 mg po q.d.); erythromycin (500 mg po q.i.d., to complete 2–3 weeks of treatment) can be substituted after there has been clinical response. Many authorities now consider azithromycin or a fluoroquinolone to be preferred for severe disease. This preference is based on results superior to those with erythromycin in animal models and, in addition, on poor tolerance of erythromycin [46, 140, 141]. FDA-approved drugs for administration against Legionella are erythromycin, azithromycin, ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, and gatifloxacin. A delay in therapy is associated with increased mortality [142]. The IDSA panel considers doxycycline, azithromycin, ofloxacin, ciprofloxacin, and levofloxacin to be preferred for legionnaires' disease, on the basis of available data (B-II). These drugs are available for oral and parenteral administration. The duration of treatment should be 10–21 days, although less for azithromycin because of its long half-life. HPS HPS is a frequently lethal systemic disease of previously healthy young adults that was originally recognized in May 1993. At least 5 viruses have been implicated [143–145]. The most common in the United States is Sin Nombre virus, which is carried by the deer mouse. Cases of HPS have been reported in nearly every region of the United States, but most cases have been found in the Four Corners area: New Mexico, Arizona, Utah, and Colorado [146]. The median age of patients for the first 100 United States cases was 35 years, and the overall case fatality rate was 52% [147]. Common features of the prodromal phase include fever, chills, myalgias, headache, nausea, vomiting, and/or diarrhea. A cough is common but is not a prominent early feature. Initial symptoms resemble those of other common viral infections. Characteristic features often become evident after the 3–6 day prodrome and include characteristic laboratory changes, chest radiographic evidence of capillary leakage (adult respiratory distress syndrome [ARDS]), and oxygen desaturation. Other, more common causes of ARDS for consideration are chronic pulmonary disease, malignancy, trauma, burns, and surgery. Among lethal cases of HPS, the median time of death is 5 days after onset of the disease. Typical laboratory findings include hemoconcentration, thrombocytopenia, leukocytosis with a left shift, and circulating immunoblasts. Additional laboratory findings include an elevated serum lactate dehydrogenase level, arterial partial pressure of oxygen 95% of patients), arterial hypoxemia, and chest radiographic evidence of bilateral interstitial infiltrates with a highly characteristic “ground glass” appearance. Up to 30% of patients have negative chest radiographs, which makes this illness the only relatively common form of pneumonia associated with false-negative chest radiographs [149]. The diagnostic yield with induced sputum averages 60% but varies greatly, depending on quality control [150]. The yield with bronchoscopy exceeds 95%. The disease is uniformly fatal if not treated. TMP-SMZ, dapsone-trimethoprim, and clindamycin-primaquine appear to be equally effective for treating patients who have moderately severe disease [151]. No currently recommended therapy for CAP is probably effective for PCP. The mortality rate among treated patients who are hospitalized is usually reported to be 15%–20%. Influenza Influenza is clearly the most common serious viral airway infection of adults in terms of morbidity and mortality. Seasonal epidemics in the United States are commonly associated with ≥20,000 deaths that are ascribed to this infection and its complications, primarily bacterial superinfections. The great pandemics of influenza in the past century were of “Spanish flu,” which in 1918 was responsible for >20 million deaths worldwide, Asian influenza (1957), and Hong Kong influenza (1968) [152]. The great majority of deaths in annual influenza epidemics are of patients who are aged >65 years, and a disproportionate number are of residents of chronic care facilities. The most common cause of bacterial superinfection is S. pneumoniae; in an era when S. aureus was the principal cause of hospital-acquired infection, this organism was prevalent [153]. Rapid identification tests are available and can lead to an etiologic diagnosis in 15–20 min with a sensitivity of 70%–90% [100]. A diagnosis can often be made with comparable sensitivity on the basis of typical symptoms in nonvaccinated patients during an influenza epidemic. In general, influenza A is more severe and shows greater antigenic heterogeneity than does influenza B. Amantadine or rimantadine appears to reduce the duration and severity of symptoms in patients with influenza A, but these drugs have no activity against influenza B [154]. Zanamivir [155–157] and oseltamivir [158] are active against influenza A and B viruses. The relative efficacy of these neuraminidase inhibitors versus that of amantadine and rimantadine for treating or preventing influenza A is unknown [158]. Clinical trials to date show that all 4 drugs reduce the duration of fever by 1–1.5 days when given within 48 h of the onset of symptoms. All 4 antimicrobial agents are also effective in influenza prevention, but the most effective prophylaxis is with annual administration of vaccine, which has been shown to have efficacy of >60% for preventing transmission in 10 of the last 11 influenza seasons. Efficacy for prevention is reduced in elderly residents of chronic care facilities, but effectiveness in preventing mortality is often reported to be 70%–80% in this latter population, depending, to some extent, on the match between the epidemic strain and the constituents of the vaccine [159]. A provocative report suggests that vaccination of health care providers in chronic care facilities is as important, or more important, than vaccination of the patients [160]. Another report showed an 88% rate of vaccine efficacy and reduced absence for respiratory illness among hospital-based health care workers [161]. These data emphasize the importance of vaccine strategies that target the populations at greatest risk, including persons aged ≥65 years, patients with cardiopulmonary disease, and residents of nursing homes and their care providers (A-I). Empyema The traditional definition of pleural empyema is pus in the pleural space. More recent investigators have used pleural fluid analyses; a pleural effusion with a pH 10 mm on a lateral decubitus radiograph [166]. Standard tests to be performed on pleural fluid include appropriate stains and culture for aerobic and anaerobic bacteria, as well as measurement of pH, lactic dehydrogenase concentration, and leukocyte and differential counts. Particularly important is the pH determination, for which the fluid must be obtained anaerobically, placed on ice, and transported immediately to the laboratory. Drainage is required when there is pus in the pleural space, a positive Gram stain or culture, or a pH 14 days' duration) [164] and then only if there is a reasonable likelihood of pertussis [182]. (The rationale for antibiotic treatment late in the course of pertussis is to reduce transmission.) The IDSA panel agrees with others in encouraging all physicians to identify methods to decrease unnecessary antimicrobial use for AB by improving their clinical approach or by communicating with patients concerning the lack of benefit, possible side effects, and development of resistance associated with such therapy [52, 166]. The practice of withholding antibiotics to most patients with cough illness is supported by the literature and is not associated with an increase in office visits [52]. The cost of follow-up visits for those patients whose conditions do not improve over a few days should be balanced against the high likelihood of spontaneous resolution and the risk to the patients and the community of unnecessary antibiotic use [165]. An exception to this admonition is consideration of an anti-influenza agent administered within 48 h of the onset of symptoms. Pneumonia in the Context of Bioterrorism There is increasing appreciation of the potential for bioterrorism, either from dissidents or from foreign countries. The relevance of this to pneumonia guidelines is based on the observation that several microbes that could be used as weapons would be expressed as pneumonia. A number of microbes could be disseminated as biological weapons by aerosol as an invisible, odorless, tasteless inoculum that could afflict as many as thousands of patients after an incubation period of days to weeks. In this setting, the etiologic agents most likely to cause severe pulmonary infection are Bacillus anthracis, Yersinia pestis, and F. tularensis [183, 184] (table 13). Recognition of these conditions would be by medical practitioners, and it is critical to implement appropriate strategies to establish the diagnosis, treat afflicted patients, and provide preventive treatment to those exposed. Thus, the “first responders” for bioterrorism are expected to be physicians in office practice, emergency rooms, ICUs, and in the discipline of infectious diseases. It should be acknowledged that national planning for a civilian medical and public health response is only now being initiated. Table 13 Biological warfare agents that would cause pulmonary disease. B. anthracis, the cause of inhalational anthrax, is one of the organisms that could be used for biological terrorism that causes the most concern because of the environmental stability of its spores, the small inoculum necessary to produce fulminant infection, and the high associated mortality rate. The incubation period is quite variable—most cases present in the first several days after exposure, but the incubation period can be ≥6 weeks [186]. The initial symptoms are nonspecific, with fever, malaise, chest pain, and a nonproductive cough. This may be followed by brief improvement and then severe respiratory distress, shock, and death. This is not a true pneumonia; chest radiographs most often show a highly characteristic widened mediastinum without parenchymal infiltrates. The diagnosis is established with positive blood cultures that may be initially dismissed as having a “Bacillus contaminant,” unless there are multiple such “contaminants” in a single facility; sputum cultures are negative. The mortality rate without treatment is >95%. In fact, the mortality rate remains >80% if treatment is not initiated before the development of clinical symptoms [187]. Administration of iv penicillin in high doses has historically been considered the preferred therapy, but reports of engineered resistance have been published. Thus, empirical treatment before sensitivity tests of the responsible strain should be oral or iv ciprofloxacin, with doxycycline or penicillin as an alternative. Sensitivity tests for initial cases may be used to dictate antibiotic choices for subsequent patients. Treatment should be continued for 60 days because of the potential problem of prolonged incubation, with delayed but equally lethal disease. Since no human-to-human transmission occurs, standard isolation precautions are appropriate. Particularly important will be prophylaxis for those who are in the region of exposure; determining the population at risk will require emergent assessment by public health officials. The preferred regimens are ciprofloxacin (500 mg po b.i.d.), doxycycline (100 mg po b.i.d.), or amoxicillin (500 mg po q8h), depending on susceptibility of the epidemic strain. Prophylaxis should be continued for 60 days. Ciprofloxacin and doxycycline are advocated, because they are highly active in vitro and have established efficacy in the animal model [186]. Other fluoroquinolones are probably equally effective. These factors are emphasized because of the possibility that regional supplies may be limited with large-scale exposures. F. tularensis causes 8-h delay from the time of admission to initiation of antibiotic therapy was associated with an increase in mortality (B-II) [188]. Antibiotic treatment should not be withheld from acutely ill patients because of delays in obtaining appropriate specimens or the results of Gram stains and cultures. Decisions regarding hospitalization based on prognostic criteria, as summarized in table 4 (A-I): in addition, this decision will be influenced by other factors, such as the availability of home support, probability of compliance, and availability of alternative settings for supervised care. Many patients with CAP are hospitalized for a concurrent disease process. Studies show that 25%–50% of admissions for CAP are for these other considerations, which extend beyond those listed as admission criteria in table 4 [10, 36]. Table 14 Pathogen-directed antimicrobial therapy for community-acquired pneumonia. Table 15 Empirical selection of antimicrobial agents for treating patients with community-acquired pneumonia. Management of Patients Who Do Not Require Hospitalization Diagnostic studies. The diagnosis of pneumonia requires the demonstration of an infiltrate on chest radiography. Posteroanterior and lateral chest radiography is recommended when pneumonia is suspected (A-II), although obtaining these radiographs may not always be practical. Additional diagnostic studies for patients who are candidates for hospitalization are summarized in table 5 (B-II). For patients who are not seriously ill and do not require hospitalization, it is desirable to perform a sputum Gram stain, with or without culture. A complete blood cell count with differential is sometimes useful to assess the illness further, in terms of detecting the severity of the infection, presence of associated conditions, and chronicity of infection. Pathogen-directed therapy. Treatment options are obviously simplified if the etiologic agent is established or strongly suspected. Antibiotic decisions based on microbial pathogens are summarized in table 14 (C-III). Empirical antibiotic decisions. The selection of antibiotics in the absence of an etiologic diagnosis (when Gram stains and cultures are not diagnostic) is based on multiple variables, including severity of the illness, the patient's age, antimicrobial intolerance or side effects, clinical features, comorbidities, concomitant medications, exposures, and epidemiological setting (B-II) (tables 7 and 15). Preferred antimicrobials. The antimicrobial agents preferred for most patients are (in no special order) a macrolide (erythromycin, clarithromycin, or azithromycin; clarithromycin or azithromycin is preferred if H. influenzae is suspected), doxycycline, or a fluoroquinolone (levofloxacin, moxifloxacin, gatifloxacin, or another fluoroquinolone with enhanced activity against S. pneumoniae). Alternative options. Amoxicillin-clavulanate and some second-generation cephalosporins (cefuroxime, cefpodoxime, and cefprozil) are appropriate for infections ascribed to S. pneumoniae or H. influenzae. These agents are not active against atypical agents. Some authorities prefer macrolides or doxycycline for patients aged 50 years or have comorbidities. Management of Patients Who Are Hospitalized Diagnostic studies. Diagnostic studies recommended for hospitalized patients are summarized in table 5 (B-II). Patients hospitalized for acute pneumonia should have blood cultures performed, preferably of specimens obtained from separate sites ≥10 min apart and before antibiotic administration (B-II). A deep-cough expectorated sputum sample procured by a nurse or physician should be obtained before antibiotic administration (B-II). This sample should be transported to the laboratory for Gram staining and culture within 2 h of collection. Testing for Legionella species, M. tuberculosis, and other pathogens should be requested when indicated. Antimicrobial treatment should be initiated promptly and should not be delayed by an attempt to obtain pretreatment specimens for microbiological studies from acutely ill patients (B-III). Induced sputum samples have established value for detection of P. carinii and M. tuberculosis, and their use generally should be limited to cases with these diagnostic considerations (A-I). Bronchoscopy or bronchoscopy with quantitative bacteriology and other invasive diagnostic techniques should be reserved for selected cases (B-III), such as pneumonia in an immunosuppressed host, suspected tuberculosis in the absence of a productive cough, chronic pneumonia, pneumonia with suspected neoplasm or foreign body, suspected PCP, or conditions that require a lung biopsy (B-II). Empirical therapy. Recommendations for empirical treatment of hospitalized patients are different in these guidelines than in the 1998 version [4]. A regimen of treatment with a β-lactam plus a macrolide or monotherapy with a fluoroquinolone is preferred. The rationale for recommending these regimens is based on studies showing that these regimens were associated with a significant reduction in mortality, compared with that associated with administration of cephalosporin alone [189]. Another study supports this observation [190]. Caution is necessary in the interpretation of these studies, since they may reflect temporal or geographic differences. These studies did not have a sufficient number of patients treated only with macrolides to justify conclusions about that category, although recent studies suggest azithromycin monotherapy is equivalent to a β-lactam or a β-lactam plus erythromycin. The recommendation of combination treatment for patients hospitalized in the ICU is based on limited data supporting monotherapy with macrolides or fluoroquinolones for patients who are critically ill with pneumococcal pneumonia. Recommendations for treating CAP that is sufficiently severe to require hospitalization in the ICU are the use of a β-lactam combined with a fluoroquinolone or a β-lactam combined with a macrolide. The goal is to provide optimal therapy for the 2 most commonly identified causes of lethal pneumonia, S. pneumoniae and Legionella. Fluoroquinolones alone are not recommended, because most therapeutic trials for these antimicrobial agents (and for macrolides) exclude seriously ill patients; thus, rigorously collected clinical data concerning seriously ill patients are limited. Preferred antimicrobials. The antimicrobial agents preferred for most patients are as follows (in no special order): in general medical wards, cefotaxime or ceftriaxone plus a macrolide (azithromycin, clarithromycin, or erythromycin) or a fluoroquinolone alone (levofloxacin, gatifloxacin, moxifloxacin, trovafloxacin, or another fluoroquinolone with enhanced activity against S. pneumoniae; fluoroquinolones with in vitro activity against most clinically significant anaerobic pulmonary pathogens include trovafloxacin, moxifloxacin, and gatifloxacin); and, in ICUs, a β-lactam (cefotaxime, ceftriaxone, ampicillin-sulbactam, or piperacillin-tazobactam) plus either a macrolide or a fluoroquinolone. Special considerations. For structural disease of the lung, such as bronchiectasis or cystic fibrosis, consider use of a regi-men that will be active against Pseudonomas aeruginosa. For β-lactam allergy, consider a regimen of fluoroquinolone with or without clindamycin. For suspected aspiration, consider a fluoroquinolone with or without a β-lactam / β-lactamase inhibitor (ampicillin-sulbactam or piperacillin-tazobactam), metronidazole, or clindamycin (some fluoroquinolones have good in vitro activity against anaerobes and may not require combination with a second antimicrobial agent [see note about fluoroquinolones in previous paragraph]). Antibiotic Considerations Antibiotics are the mainstay of treatment for pneumonia. Guidelines for their selection, summarized in tables 14 (B-II) and 15 (B-II), are based largely on clinical experience and/or in vitro activity. Treatment options are simplified if an etiologic diagnosis is established or highly suspect on the basis of results of rapid tests, such as Gram staining or use of other special stains, antigen detection, or amplification techniques (table 14). The selection of antimicrobial agents is based on multiple variables, including severity of illness, the patient's age, ability to tolerate side effects, clinical features, comorbidity, prior exposure, epidemiological setting, and cost (table 7), as well as the prevalence of drug resistance among respiratory tract patho-gens. Suggested regimens for consideration for empirical administration to patients hospitalized for acute pneumonia are summarized in table 15, with a distinction between regimens for general use and regimens for patients who require treatment in the ICU (B-II). The following discussion reviews salient issues. β-Lactams and related agents. All β-lactams exert their antibacterial effects by interfering with synthesis of the peptidoglycan component of the bacterial cell wall. The β-lactams are inactive against M. pneumoniae and C. pneumoniae, and are ineffective in the treatment of Legionella. The antibacterial spectrum of the penicillins varies from narrow-spectrum agents with activity largely limited to gram-positive cocci (penicillin G, penicillin V, and oxacillin) to expanded-spectrum agents with activity against many gram-negative bacilli (piperacillin, ticarcillin, and mezlocillin). Parenteral penicillin G, parenteral cefotaxime, parenteral ceftriaxone, and oral amoxicillin are generally viewed as the β-lactam drugs of choice for treating infections with S. pneumoniae, against which penicillin MICs are ≤1.0 µg/mL [108–111]. Alternatives to penicillin are generally preferred for infections that involve S. pneumoniae resistant to penicillin (MIC, ≥2 µg/mL), including ampicillin, cefotaxime, and ceftriaxone. Penicillins combined with β-lactamase inhibitors (amoxicillin-clavulanate, ticarcillin-clavulanate, ampicillin-sulbactam, and piperacillin-tazobactam) are active against β-lactamase-producing organisms, such as H. influenzae, anaerobes, and M. catarrhalis, but these combinations offer no advantage over penicillin G against S. pneumoniae. Ticarcillin has less activity than other penicillins against S. pneumoniae. Cephalosporins. These drugs generally show enhanced activity against aerobic gram-negative bacilli as when going from first- to second- to third-generation agents. The antimicrobial agents in this class most active against strains of S. pneumoniae are cefotaxime and ceftriaxone [53, 106, 107], and the clinical relevance of in vitro resistance to these drugs for treating pneumonia has been questioned. Cefuroxime is substantially less active in vitro than cefotaxime and ceftriaxone and has been anecdotally associated with treatment failures [191]. Parenteral cephalosporins that should not be used for pneumococcal pneumonia include first-generation agents, such as cefazolin and cephalexin, and third-generation drugs, such as ceftizoxime and ceftazidime. Oral cephalosporins that are preferred on the basis of their in vitro activity against S. pneumoniae are cefuroxime, cefpodoxime, and cefprozil. Most second- and third-generation cephalosporins show moderate to good activity against H. influenzae and M. catarrhalis. Cephalosporins with the best in vitro activity against anaerobic gram-negative bacilli (Prevotella and Bacteroides species) are cefoxitin, cefotetan, and cefmetazole, although there are no published studies of the use of these drugs for anaerobic lung infections. Other cephalosporins are less active against anaerobes in vitro. Carbapenems. Meropenem and imipenem are active against a broad spectrum of aerobic and anaerobic gram-positive and gram-negative organisms, including most strains of S. pneumoniae and P. aeruginosa, and virtually all strains of H. influenzae, M. catarrhalis, anaerobes, and methicillin-susceptible S. aureus. Activity against penicillin-resistant S. pneumoniae is generally adequate. Macrolides. Erythromycin has a limited antimicrobial spectrum of activity and is poorly tolerated because of gastrointestinal side effects. Newer macrolides that are better tolerated but more expensive include azithromycin and clarithromycin. All 3 appear to be effective for treating pulmonary infections caused by M. pneumoniae, C. pneumoniae, and Legionella. About 5% of penicillin-resistant S. pneumoniae isolates are resistant to macrolides in vitro; this rate is substantially higher for strains with intermediate- or high-level penicillin resistance [43, 107, 111], so caution is necessary with empirical use in suspected cases of pneumococcal pneumonia. There are 2 mechanisms of macrolide resistance by S. pneumoniae. First, the M phenotype, because of an efflux mechanism, is associated with MICs of 2–8 µg/mL and, in theory, may be overcome by high doses; this mechanism is prevalent in the United States. Second, the ERM phenotype, due to ribosomal alterations, is associated with MICs ≥64 µg/mL; this mechanism predominates in Europe. Cases of macrolide failure have been described anecdotally but have been infrequent so far [114]. Macrolides have reasonably good activity against anaerobes, except for fusobacteria. Community-acquired strains of S. aureus are usually susceptible to macrolides. Most bacteria are susceptible or resistant to all 3 macrolides, but there are some differences. Erythromycin is relatively inactive against H. influenzae. Clarithromycin also has relatively limited in vitro activity against H. influenzae; however, its 14-OH metabolite augments the activity of the parent compound [192, 193]. Of the 3 macrolides, azithromycin is the most active agent in vitro against Legionella, H. influenzae, and M. pneumoniae, whereas clarithromycin is the most active against S. pneumoniae and C. pneumoniae. Azithromycin and erythromycin are available for iv administration. A multicenter prospective study of 864 immunocompetent outpatients with CAP showed erythromycin to be cost-effective antimicrobial therapy [194], and a recent trial showed monotherapy with iv azithromycin was equivalent to a regimen of cefuroxime with or without erythromycin for patients hospitalized with CAP [195]. The IDSA panel felt the latter report supported azithromycin for initial empirical treatment, but concern was expressed that most of the participants were not very ill, the comparator arm was not ideal, and in vitro activity of azithromycin against S. pneumoniae was suboptimal. Quinolones. Currently available agents in this class for pulmonary infections are ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, moxifloxacin, gatifloxacin, and trovafloxacin. These drugs are active in vitro against most clinically significant aerobic gram-positive cocci, gram-negative bacilli, H. influenzae, M. catarrhalis, Legionella species, M. pneumoniae, and C. pneumoniae. Levofloxacin, sparfloxacin, moxifloxacin, gatifloxacin, and trovafloxacin show enhanced in vitro activity against S. pneumoniae, including penicillin-resistant strains [49, 107– 111], and initial clinical trials show good results [196, 197]. One study showed clinical outcomes with levofloxacin were significantly better than with a cephalosporin regimen for empirical treatment of CAP [196]. Trovafloxacin has been associated with excessive rates of hepatotoxicity, so its use is generally restricted to hospitalized patients who lack alternative antibiotic options. Sparfloxacin has high rates of photosensitivity reactions and higher rates of QT-interval prolongation than other fluoroquinolones. Ciprofloxacin is slightly less active in vitro, and there are anecdotal reports of clinical failures for pneumococcal pneumonia; some authorities feel that a dosage of 750 mg twice daily is adequate for empirical use. Support for the concern about increasing resistance by S. pneumoniae is found in reports of increases in the MICs of fluoroquinolones against sequentially collected strains of S. pneumoniae in Hong Kong [116], England [117], Ireland [118], and Canada [115]. Ciprofloxacin, ofloxacin, levofloxacin, gati-floxacin, and trovafloxacin are available for iv administration. Aminoglycosides. The aminoglycosides (gentamicin, tobramycin, netilmicin, and amikacin) show a concentration-dependent bactericidal effect that permits a single-daily-dose regimen. These agents are active in vitro against the aerobic and facultative gram-negative bacilli, including P. aeruginosa. Some authorities feel aminoglycosides should not be used as single agents for treating gram-negative bacillary pneumonia. Poor clinical results may be due to suboptimal dosing or to possible inactivation of the drug by the acidic environment at the site of infection [198, 199]. Tetracyclines. There are multiple members of this class, but the one most frequently used in clinical practice today is doxycycline, on the basis of tolerance, convenience of twice-daily dosing, good bioavailability, and low price [200]. Among respiratory tract pathogens, the tetracyclines are active in vitro against the “atypical” organisms, including M. pneumoniae, C. pneumoniae, and Legionella [196]. S. pneumoniae and H. influenzae in the past have been quite susceptible to these agents [201, 202], but ∼15% of pneumococci are now resistant [49, 107–112, 197, 198]. Vancomycin. Vancomycin shows universal activity against S. pneumoniae [49, 107–112]. It is also active against other gram-positive organisms, including methicillin-resistant S. aureus. There is substantial concern about excessive vancomycin use because it promotes the evolution of enterococci that are resistant to vancomycin and of S. aureus strains that are only intermediately susceptible. Pneumococcal tolerance of vancomycin has also recently been described, although the clinical relevance of this finding is unknown. Clindamycin. Clindamycin exhibits good in vitro activity against gram-positive cocci, including pneumococci that resist macrolides by the efflux pump mechanism and most methicillin-susceptible S. aureus [107–112, 200 203]. Many authorities consider clindamycin to be the preferred drug for anaerobic pulmonary infections, including aspiration pneumonia and putrid lung abscess [125, 128–131]. It is inactive against H. influenzae, atypical etiologic agents, and a varying proportion of erythromycin-resistant S. aureus. TMP-SMZ. TMP-SMZ is active in vitro against a broad spectrum of gram-positive and gram-negative organisms but has increasingly lost its efficacy against S. pneumoniae [49, 107–112]. About 20%–25% of S. pneumoniae strains are resistant, and >70% of penicillin-resistant S. pneumoniae isolates are not susceptible to TMP-SMZ. TMP-SMZ is active against such diverse pathogens as Nocardia asteroides, P. carinii, and Steno-trophomonas maltophilia. Antiviral agents. Amantadine and rimantadine are inhibitors of hemagglutinin that have established efficacy in treating and preventing influenza A [154]. Relenza and oseltamivir have established efficacy for treatment of influenza A and B and also appear effective for prevention [155–158]. For treatment, all 4 of these drugs must be given within 40–48 h of the onset of influenza symptoms. Therapeutic trials show a mean reduction in the duration of influenza symptoms, including fever of ∼1–1.5 days and a substantial reduction in viral shedding. Amantadine and rimantadine are comparably effective in comparative trials; rimantadine is more expensive but has less CNS toxicity. Relenza and oseltamavir are recently FDA-approved neuraminidase inhibitors that appear equally effective, although no trials comparing these drugs with each other or these drugs with amantadine and rimantadine have been reported. Possible advantages of the neuraminidase inhibitors are the additional activity against influenza B, lack of CNS toxicity, and reduced probability of resistance; disadvantages are the higher price, the somewhat awkward aerosol-delivery device for and possible wheezing with relenza, and gastrointestinal side effects of oseltamivir. The IDSA panel endorses the use of these antiviral agents for treating influenza (B-I). The need to initiate therapy within 40–48 h requires a rapid diagnostic test for influenza detection or empirical treatment based on typical clinical features in an influenza epidemic. The 4 drugs for influenza A appear equally effective; therefore, selection should be based on availability, toxicity, and cost. Length and Route of Treatment We are not aware of any controlled trials that have specifically addressed the question of how long pneumonia should be treated. This decision is usually based on the pathogen, response to treatment, comorbid illness, and complications. Until further data are forthcoming, it seems reasonable to treat pneumonia caused by S. pneumoniae until the patient has been afebrile for 72 h (C-III). Pneumoniae caused by bacteria that can necrose pulmonary parenchyma (e.g., S. aureus, P. aeruginosa, Klebsiella, and anaerobes) should probably be treated for ≥2 weeks. Pneumonia caused by M. pneumoniae or C. pneumoniae [204–206] should probably be treated for at least 2 weeks, as should legionnaires' disease in immunocompetent individuals (B-II). Azithromycin may be used for shorter courses of treatment because of its very long half-life in tissues [207]. As cost considerations and pressure to treat patients with pneumonia outside the hospital increase, there is rising interest in the use of oral therapy. For many drugs that are well absorbed from the gut, there is no clear advantage of parenteral therapy. Nevertheless, for most patients admitted to the hospital, common practice is at least to begin therapy with iv drugs. Although no studies verify a superior outcome, this practice is justified by concern for absorption in acutely ill patients. Changing from iv to oral therapy is associated with a number of economic, health care, and social benefits. It reduces costs of treatment and shortens length of hospital stay. Numerous randomized controlled trials support this practice [19], providing that the patient's condition is improving clinically and is hemodynamically stable, the patient is able to ingest drugs, and the gastrointestinal tract is functioning normally (A-I). In most cases, these conditions are met within 3 days, and oral therapy can be given at that time. Ideally, the drug that was given parenterally or a closely related one is given orally; if no such oral formulation is available, an oral agent with a similar spectrum of activity should be selected on the basis of in vitro or predicted sensitivity patterns of the established or probable pathogen. As a general matter, the IDSA panel endorses use of bioavailable and active oral antimicrobial agents for patients whose medical conditions are stable and who tolerate these drugs (A-III). Assessment of response to treatment. The expected response to treatment should take into account the immunologic capacity of the host, the severity of the illness, the pathogen, and the chest radiographic findings. Subjective response is usually noted within 1–3 days of initiation of treatment. Objective parameters include respiratory symptoms (cough, dyspnea), fever, partial pressure of oxygen, peripheral leukocyte count, and findings on serial radiographs. The most carefully documented response is fever or time to defervescence. With pneumococcal pneumonia in young adults, the average duration of fever after treatment is 2.5 days; in bacteremic pneumonia cases, it is 6–7 days; and in elderly patients who are febrile, it also appears to be longer. Patients with M. pneumoniae are usually afebrile within 1–2 days after treatment, whereas immunocompetent patients with legionnaires' disease defervesce in an average of 5 days. Blood cultures in cases of bacteremic pneumonia are usually negative within 24–48 h of treatment. The pathogen is usually also suppressed in respiratory secretions within 24–48 h; the major exceptions are P. aeruginosa (or other gram-negative bacilli), which may persist despite appropriate treatment, and M. pneumoniae, which usually persists despite effective therapy. Follow-up cultures of blood and sputum are not indicated for patients who respond to therapy, except for those with tuberculosis. Chest radiographic findings usually clear more slowly than clinical findings, and multiple radiographs are generally not required (A-II) [65]. During the first several days of treatment, there is often radiographic progression despite a good clinical response, presumably reflecting continued inflammatory changes, even in the absence of viable bacteria. Follow-up radiography during hospitalization may be indicated to assess the position of an endotracheal tube, to assess the position of a line, and to exclude pneumothorax after central line placement or to determine reasons for failure to respond, such as pneumothorax, empyema, progression of infiltrate, cavitation, pulmonary edema, or ARDS. With regard to host factors, age and presence or absence of comorbid illness are important determinants of the rate of reso-lu-tion. Radiographs of most patients with bacteremic pneumococcal pneumonia who are aged 40 years and/or smokers, to document resolution of infiltrates and to exclude underlying diseases such as neoplasm. Patients who fail to respond. When patients fail to respond or their conditions deteriorate after initiation of empirical therapy, a number of possibilities should be considered (figure 3) (C-III). Incorrect diagnosis (not an infection or underlying noninfectious disease with infectious component): noninfectious illnesses that may account for the clinical and radiographic findings include congestive heart failure, pulmonary embolus, atelectasis, sarcoidosis, neoplasms, radiation pneumonitis, pulmonary drug reactions, vasculitis, ARDS, pulmonary hemorrhage, and inflammatory lung disease. Correct diagnosis: if a correct diagnosis has been made, but the patient fails to respond, the physician should consider each of the following components of the host-drug-pathogen triad. Host-related problem: the overall reported mortality for hospitalized patients with CAP is 10%–15%; this figure includes patients with an established or likely etiologic diagnosis who are treated with appropriate antibiotics [9]. The mortality rate for patients with bacteremic pneumococcal pneumonia caused by penicillin-susceptible strains of S. pneumoniae and treated with penicillin has been consistently reported at ≥20% [121]. The usual explanation is that physiological events, often in the form of cascades, have been set in motion and are not reversed by simply killing the infecting organism. Occasional patients have local lesions that preclude optimal response, such as obstruction by a neoplasm or a foreign body. Empyema is an infrequent but important cause of failure to respond. Other complications include adverse drug reactions, other complications of medical management such as fluid overload, pulmonary superinfection or sepsis from an iv line, or any of a host of medical complications related to hospitalization. Drug-related problem: whether a specific pathogen has been isolated, if a correct etiologic diagnosis of pneumonia has been made, but the patient does not appear to be responding, the physician should always consider the possibility of a medication error, an inappropriate dosing regimen, a problem with compliance, malabsorption, a drug-drug interaction that reduces antimicrobial levels, or other factors that may alter drug delivery to the site of infection. Drug fever or another adverse drug reaction may obscure response to successful therapy. Pathogen-related problem: the causative organism may have been identified correctly but may be resistant to the antibiotic administered. Examples might include a penicillin-resistant pneumococcus, methicillin-resistant S. aureus, or a multiresistant gram-negative-bacillus rod. The wide variety of other pathogens that might not be identified and would not be expected to respond to some or all of the regimens recommended for empirical use include M. tuberculosis, fungi, viruses, Nocardia, C. psittaci, hantavirus, C. burnetii, or P. carinii. In some cases, these or other organisms may represent copathogens. Assessment of a nonresponding patient: the assessment of a patient who fails to respond to initial empirical therapy should take into account the possibilities outlined above and in figure 3. Tests appropriate to the individual disease entities should be used to exclude noninfectious possibilities. Specific examples include ventilation-perfusion lung scans and, in selected cases, pulmonary angiography to identify pulmonary embolus, identification of antineutrophil cytoplasmic antibody, and bronchoscopy or open-lung biopsy to diagnose a variety of noninfectious causes. Some host factors that might influence the range of pathogens, as well as the response, include HIV infection, cystic fibrosis, neoplasms, recent travel, and unusual exposures. For those cases in which infection is responsible for the clinical and radiographic findings, issues relating to the host-drug-pathogen triad should be taken into account during the work up. To rule out an endobronchial lesion or foreign body, bronchoscopy and/or CT scanning may be of help. To ensure that a sequestered focus of infection, such as a lung abscess or empyema, has not developed, thereby preventing access of the drugs to the pathogens, CT scanning of the chest may be useful. For pleural effusions detected on chest radiograph, ultrasonography can localize the collection and provide an estimate of the volume of fluid. Infection caused by an unsuspected organism or a resistant pathogen must always be a concern with regard to the nonresponding patient. An aggressive attempt to obtain appropriate expectorated sputum samples may lead to identification of such organisms on stain or culture, although the validity of such posttreatment specimens must be questioned because of the inability to culture S. pneumoniae and other fastidious patho-gens and frequent overgrowth by S. aureus and gram-negative bacilli. In selected cases, bronchoscopy may be necessary; 1 study suggested that helpful information may be provided by this procedure for up to 41% of patients with CAP whose initial empirical antimicrobial therapy fails [73]. Prevention of CAP The annual impact of influenza is highly variable. During winters when influenza is epidemic, its impact on CAP is sizable as a result of both primary influenza pneumonia and secondary bacterial pneumonia. Influenza vaccine is effective in limiting severe disease caused by influenza virus [158] and is recommended to be given annually to persons at increased risk for complications, as well as to health care workers (A-I) [106]. Polyvalent vaccines of pneumococcal capsular polysaccharides have been shown to be effective in preventing pneumococcal pneumonia in American military recruits [210] and in young adult African males [211]. The currently available 23-valent vaccine is ∼60% effective in preventing bacteremic pneumococcal infection in immunocompetent adults [212, 213]. Efficacy tends to decline with age and may be unmeasurable in immunocompromised hosts [214, 215]. Despite controversies over efficacy [215–217], the fatality rate of bacteremic pneumococcal infection among those aged >64 years and/or with a variety of underlying systemic illnesses remains high, the potential for benefit in individual cases cannot be denied, and the vaccine is essentially free of serious side effects. Accordingly, the IDSA panel endorses current CDC guidelines for pneumococcal vaccine (B-II). More than half of patients hospitalized with pneumococcal disease have had other hospitalizations within the previous 5 years [218]. Unvaccinated patients with risk factors for pneumococcal disease and influenza should consequently be vaccinated during hospitalization whenever possible (C-III). There is no contraindication for use of either pneumococcal or influenza vaccine immediately after an episode of pneumonia (i.e., before hospital discharge). The vaccines are inexpensive and can be given simultaneously. Performance Indicators The following are recommended performance indicators: (1) blood cultures before antibiotic therapy for hospitalized patients (studies indicate that compliance with this recommendation is associated with a significant reduction in mortality [67]); (2) initiation of antibiotic therapy within 8 h of hospitalization (prior studies indicate that compliance with this recommendation is associated with a significant reduction in mortality [183]); (3) use of culture and/or urinary antigen testing for detecting Legionella species in 50% of patients hospitalized in the ICU for enigmatic CAP; (4) demonstration of an infiltrate by chest radiography or other imaging technique for all patients with an ICD-9-code diagnosis of CAP who do not have AIDS or neutropenia; and (5) measurement of blood gases or performance of pulse oximetry before admission or within 8 h of admission.
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                Contributors
                stephen72mshana@gmail.com
                Journal
                Pneumonia (Nathan)
                Pneumonia (Nathan)
                Pneumonia
                BioMed Central (London )
                2200-6133
                5 August 2020
                5 August 2020
                2020
                : 12
                Affiliations
                [1 ]Department of Internal Medicine, Weill Bugando School of Medicine, Mwanza, Tanzania
                [2 ]National Health Laboratory Quality Assurance and Training Centre, Dar es Salaam, Tanzania
                [3 ]Department of Microbiology/Immunology, Weill Bugando School of Medicine, Mwanza, Tanzania
                Article
                69
                10.1186/s41479-020-00069-0
                7409501
                32775174
                © The Author(s) 2020

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