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BACKGROUND: Patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP) experience recurrent respiratory tract infections. Dupilumab targets type 2 inflammation, a common underlying pathophysiology of both conditions, with proven efficacy. OBJECTIVE: To examine investigator-reported respiratory infection adverse events and anti-infective medication use with dupilumab versus placebo in patients with moderate-to-severe asthma or severe CRSwNP. METHODS: We performed a post hoc analysis of the pivotal phase 3 trials LIBERTY ASTHMA QUEST (NCT02414854) and LIBERTY NP SINUS-52 (NCT02898454) in moderate-to-severe asthma and severe CRSwNP, respectively. RESULTS: Investigator-reported respiratory infection events occurred at a significantly lower incidence in patients treated with dupilumab versus placebo, in both asthma (22% lower; P < .0001; 95% CI 0.71-0.85) and CRSwNP (38% lower; P

Background Community-acquired pneumonia (CAP) guidelines have improved the treatment and outcomes of patients with CAP, primarily by standardization of initial empirical therapy. But current society-published guidelines exclude immunocompromised patients. Research Question There is no consensus regarding the initial treatment of immunocompromised patients with suspected CAP. Study Design and Methods This consensus document was created by a multidisciplinary panel of 45 physicians with experience in the treatment of CAP in immunocompromised patients. The Delphi survey methodology was used to reach consensus. Results The panel focused on 21 questions addressing initial management strategies. The panel achieved consensus in defining the population, site of care, likely pathogens, microbiologic workup, general principles of empirical therapy, and empirical therapy for specific pathogens. Interpretation This document offers general suggestions for the initial treatment of the immunocompromised patient who arrives at the hospital with pneumonia.

Summary Background Treatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to established guidelines. Therefore, we aimed to investigate the efficacy of the combination drug device Amikacin Inhale as an adjunctive therapy to intravenous standard-of-care antibiotics for pneumonia caused by Gram-negative pathogens in intubated and mechanically ventilated patients. Methods INHALE was a prospective, double-blind, randomised, placebo-controlled, phase 3 study comprising two trials (INHALE 1 and INHALE 2) done in 153 hospital intensive-care units in 25 countries. Eligible patients were aged 18 years or older; had pneumonia that had been diagnosed by chest radiography and that was documented as being caused by or showing two risk factors for a Gram-negative, multidrug-resistant pathogen; were intubated and mechanically ventilated; had impaired oxygenation within 48 h before screening; and had a modified Clinical Pulmonary Infection Score of at least 6. Patients were stratified by region and disease severity (according to their Acute Physiology and Chronic Health Evaluation [APACHE] II score) and randomly assigned (1:1) via an interactive voice-recognition system to receive 400 mg amikacin (Amikacin Inhale) or saline placebo, both of which were aerosolised, administered every 12 h for 10 days via the same synchronised inhalation system, and given alongside standard-of-care intravenous antibiotics. All patients and all staff involved in administering devices and monitoring outcomes were masked to treatment assignment. The primary endpoint, survival at days 28–32, was analysed in all patients who received at least one dose of study drug, were infected with a Gram-negative pathogen, and had an APACHE II score of at least 10 at diagnosis. Safety analyses were done in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , numbers NCT01799993 and NCT00805168 . Findings Between April 13, 2013, and April 7, 2017, 807 patients were assessed for eligibility and 725 were randomly assigned to Amikacin Inhale (362 patients) or aerosolised placebo (363 patients). 712 patients received at least one dose of study drug (354 in the Amikacin Inhale group and 358 in the placebo group), although one patient assigned to Amikacin Inhale received placebo in error and was included in the placebo group for safety analyses. 508 patients (255 in the Amikacin Inhale group and 253 in the placebo group) were assessed for the primary endpoint. We found no between-group difference in survival: 191 (75%) patients in the Amikacin Inhale group versus 196 (77%) patients in the placebo group survived until days 28–32 (odds ratio 0·841, 95% CI 0·554–1·277; p=0·43). Similar proportions of patients in the two treatment groups had a treatment-emergent adverse event (295 [84%] of 353 patients in the Amikacin Inhale group vs 303 [84%] of 359 patients in the placebo group) or a serious treatment-emergent adverse event (101 [29%] patients vs 97 [27%] patients). Interpretation Our findings do not support use of inhaled amikacin adjunctive to standard-of-care intravenous therapy in mechanically ventilated patients with Gram-negative pneumonia. Funding Bayer AG.

Objectives Community-acquired pneumonia (CAP) is an important complication in patients with chronic obstructive pulmonary disease (COPD). This study aimed to define incidence, and outcomes of COPD patients hospitalized with pneumonia in the city of Louisville, and to estimate the burden of disease in the US population. Methods This was a secondary analysis of a prospective population-based cohort study of residents in Louisville, Kentucky, 40 years old and older, from 1 June 2014 to 31 May 2016. All adults hospitalized with CAP were enrolled. The annual incidence of pneumonia in COPD patients in Louisville was calculated and the total number of adults with COPD hospitalized in the United States was estimated. Clinical outcomes included time to clinical stability (TCS), length of hospital stay (LOS) and mortality. Results From a Louisville population of 18 246 patients with COPD, 3419 pneumonia hospitalizations were documented during the 2-year study. The annual incidence was 9369 patients with pneumonia per 100 000 COPD population, corresponding to an estimated 506 953 adults with COPD hospitalized due to pneumonia in the United States. The incidence of CAP in patients without COPD was 509 (95% CI 485–533) per 100 000. COPD patients had a median (interquartile range) TCS and LOS of 2 (1–4) and 5 (3–9) days respectively. The mortality of COPD patients during hospitalization, at 30 days, 6 months and 1 year was 193 of 3419 (5.6%), 400 of 3374 (11.9%), 816 of 3363 (24.3%) and 1104 of 3349 (33.0%), respectively. Conclusions There was an annual incidence of 9369 cases of hospitalized CAP per 100 000 COPD patients in the city of Louisville. This was an approximately 18-fold greater incidence of CAP in COPD patients than in those without COPD.

Summary A subgroup of patients admitted to the hospital with a diagnosis of community-acquired pneumonia (CAP) have received antibiotic therapy prior to admission for the current episode of pneumonia. The objective of this study was to assess the clinical course of patients receiving antibiotics prior to admission, compared to patients not previously treated. An observational cohort of 3364 CAP patients consecutively admitted to our hospital, and prospectively included, were studied. We collected clinical, microbiological and biochemical parameters, focusing on recent antibiotics received prior to admission. 610 (18%) patients received antibiotics prior to hospital admission for the current CAP episode. Patients with previous antibiotic use developed septic shock less frequently (4% vs. 7%, p = 0.007) and required invasive ventilation less often (3% vs. 6%, p = 0.002). After adjustment by different covariate factors and propensity score, antibiotic therapy was still independently associated with a lower incidence of septic shock at admission (OR 0.54 [95% CI 0.31–0.95], p = 0.03) and less need for invasive ventilation (OR 0.38 [95% CI 0.16–0.91], p = 0.03). In this cohort, recent use of antibiotics before hospital admission in CAP seems to be associated with a lower incidence of septic shock on admission and a lower need for invasive ventilation.

Background In Japan, the routine use of early antiviral therapy for patients with influenza is standard. Methods This multicenter prospective cohort evaluation of hospitalized patients with laboratory-confirmed influenza identified prognostic factors among the patients receiving antiviral therapy. Results Of 1,345 patients with influenza (766 pediatric, 579 adult), excluding those aged Streptococcus pneumoniae (12.3%); Staphylococcus aureus (10.9%), including methicillin-resistant S aureus (MRSA) 3.3%; Enterobacteriaceae (8.1%); and Pseudomonas aeruginosa (3.3%). Of the adult patients, 151 were classified as having community-acquired pneumonia (CAP) and 60 as having health-care-associated pneumonia (HCAP). Inappropriate therapy was more common in HCAP than in CAP (15.2% vs 2%, P = .001). Potential multidrug-resistant (MDR) pathogens were more common (21.7% vs 2.6%, P P = .002) and P aeruginosa (8.3% vs 1.3%, P = .021). Using Cox proportional hazards modeling with prescribed independent variables, male sex, severity score, serum albumin levels (malnutrition), and pneumonia were associated with survival 30 days from the onset of influenza. Conclusions Among the prognostic factors, malnutrition and pneumonia are amenable to medical intervention. An opportunity exists to improve empirical therapy for patients with HCAP and influenza. Trial Registry Japan Medical Association Center for Clinical Trials; No.: JMA-IIA00123; URL: http://www.jmacct.med.or.jp/en/

Nosocomial pneumonia remains a significant cause of hospital-acquired infection, imposing substantial economic burden on the health care system worldwide. Various preventive strategies have been increasingly used to prevent the development of pneumonia. It is now recognized that patients with health care-associated pneumonia are a heterogeneous population and that not all are at risk for infection with nosocomial pneumonia pathogens, with some being infected with the same organisms as in community-acquired pneumonia. This review discusses the risk factors for nosocomial pneumonia, controversies in its diagnosis, and approaches to the treatment and prevention of nosocomial and health care-associated pneumonia.

Biomarkers have been proposed as tools that can guide the management of patients with community-acquired pneumonia, providing information that supplements the usually available clinical data. Among the available biomarkers, procalcitonin has been studied extensively and seems promising for several purposes. The use of biomarkers needs further study, to validate their utility in daily practice, especially given the limitations of the current tools for identifying the need for antibiotic therapy in patients with influenza and secondary bacterial pneumonia, in patients with aspiration syndromes, and in those infected with atypical pathogens.

Although pregnancy is infrequently complicated by pneumonia, lung infection by bacteria, viruses, and fungi can pose serious maternal and fetal hazards. Pneumonia may lead to preterm labor and certain infecting agents, most notably the HIV virus, can cross the placenta and lead to neonatal infection. There is some evidence that the incidence of pneumonia in pregnancy may be increasing among certain populations. In addition, infections caused by viruses (varicella and influenza) and fungal agents, ordinarily controlled by cell-mediated immunity, may be more virulent to pregnant women, thereby adding to maternal mortality. Beyond the influence of these pregnancy-induced changes in immunity, there are certain physiologic changes in pregnancy that make it more difficult for the pregnant woman to sustain any type of respiratory infectious insult. Certain types of pneumonias, particularly influenza and aspiration, may be avoided if patients at risk are identified and existing strategies for prevention are applied. When the pregnant women is treated for lung infection, the safety of antimicrobial agents must be considered, and therapy may differ from that used in the nonpregnant patient.

Pneumonia is a major cause of morbidity and mortality among nursing home residents. The approach to managing these patients has lacked uniformity because of the paucity of clinical trials, complexity of underlying comorbid diseases, and heterogeneity of administrative structures. The decision to hospitalize nursing home patients with pneumonia varies among institutions depending on staffing level, availability of diagnostic testing, and laboratory support. In the absence of comparative studies, choice of empirical antibiotic therapy continues to be based on expert opinion. Validated prognostic scoring models are needed for risk stratification. Pneumococcal and influenza vaccination are the primary prevention measures. As of January 2010, Medicare no longer pays for consultation codes; thus, practitioners must instead use existing evaluation and management service codes when providing these services.

This article examines the bacteriology, clinical features, therapy for, and prevention of pneumonia in older patients. The discussion focuses on patients who develop pneumonia out of the hospital, including individuals with community-acquired pneumonia and health care-associated pneumonia. Health care-associated pneumonia incorporates patients who live in nursing homes when they develop pneumonia and in many instances requires management similar to nosocomial pneumonia. We have chosen not to discuss nosocomial pneumonia in older patients because it does not have distinctive features or a different management approach than when this illness arises in younger patients.

Background Community-acquired pneumonia (CAP) with a pneumonia severity index (PSI) score in risk class V (PSI-V) is a potentially life-threatening condition, yet the majority of patients are not admitted to the ICU. The aim of this study was to characterize CAP patients in PSI-V to determine the risk factors for ICU admission and mortality, and to assess the performance of CAP severity scores in this population. Methods Prospective observational study including hospitalized adults with CAP in PSI-V from 1996 to 2003. Clinical and laboratory data, microbiological findings, and outcomes were recorded. The PSI score; modified American Thoracic Society (ATS) score; the confusion, urea, respiratory rate, low BP (CURB) score, and CURB plus age of ≥ 65 years score were calculated. A reduced score based on the acute illness variables contained in the PSI was also obtained. Results A total of 457 patients were included in the study (mean [± SD] age, 79 ± 11 years), of whom 92 (20%) were admitted to the ICU. Patients in the ward were older (mean age, 82 ± 10 vs 70 ± 10 years, respectively) and had more comorbidities. ICU patients experienced significantly more acute organ failures. The mortality rate was higher in ICU patients, but also was high for non-ICU patients (37% vs 20%, respectively; p=0,003). A low level of consciousness (odds ratio [OR], 3.95; 95% confidence interval [CI], 2 to 5) and shock (OR, 24.7; 95% CI, 14 to 44) were associated with a higher risk of death. The modified ATS severity rule had the best accuracy in predicting ICU admission and mortality. Conclusions Most CAP patients PSI-V were treated on a hospital ward. Those admitted to the ICU were younger and had findings of more acute illness. The PSI performed well as a mortality prediction tool but was less appropriate for guiding site-of-care decisions.

Background and study objectives: The range and relative impact of microbial pathogens, particularly viral pathogens, as a cause of community-acquired pneumonia (CAP) in hospitalized adults has not received much attention. The aim of this study was to determine the microbial etiology of CAP in adults and to identify the risk factors for various specific pathogens. Methods: We prospectively studied 176 patients (mean [± SD] age, 65.8 ± 18.5 years) who had hospitalized for CAP to identify the microbial etiology. For each patient, sputum and blood cultures were obtained as well as serology testing for Mycoplasma pneumoniae and Chlamydophila pneumoniae , urinary antigen testing for Legionella pneumophila and Streptococcus pneumoniae , and a nasopharyngeal swab for seven respiratory viruses. Results: Microbial etiology was determined in 98 patients (55%). S pneumoniae (49 of 98 patients; 50%) and respiratory viruses (32%) were the most frequently isolated pathogen groups. Pneumococcal pneumonia was associated with tobacco smoking of > 10 pack-years (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.2 to 5.4; p = 0.01). Respiratory viruses were isolated more often in fall or winter (28%; p = 0.011), and as an exclusive etiology tended to be isolated in patients ≥ 65 years of age (20%; p = 0.07). Viral CAP was associated with antimicrobial therapy prior to hospital admission (OR, 4.5; 95% CI, 1.4 to 14.6). Conclusions: S pneumoniae remains the most frequent pathogen in adults with CAP and should be covered with empirical antimicrobial treatment. Viruses were the second most common etiologic agent and should be tested for, especially in fall or winter, both in young and elderly patients who are hospitalized with CAP.

Many antibiotics, including macrolides and quinolones, are used incorrectly in the treatment of presumed respiratory tract infections. The use of broad-spectrum antibiotics increased considerably in the 1990s, but often this use is inappropriate. Guidelines, such as those for community-acquired pneumonia, encourage rational therapy and more prudent prescribing. There are strong links between appropriate use, compliance and resistance as well as between regimen complexity and compliance. These issues provide a platform for thinking about a short-duration, high-compliance drug therapy with good clinical efficacy. Such therapy will need to be combined with programs to promote rational antibiotic use, particularly targeting inappropriate prescribing for viral infections and use of agents with a broader antimicrobial spectrum than is necessary.

Community-acquired pneumonia (CAP) is a common disorder that is potentially life-threatening, especially in older adults and patients with comorbid disease. Despite substantial progress in therapeutic options, CAP remains a primary cause of death from infectious disease in the United States. The mainstay of treatment for most patients is appropriate antimicrobial therapy This article reviews the principles for initial antimicrobial therapy, highlights some of the differences in approaches to antimicrobial drug selection in selected guidelines, and includes new recommendations for empiric and pathogen-directed therapy of CAP.

Community-acquired pneumonia (CAP) is a costly disease that is associated with significant morbidity and mortality. The growing prevalence of this disease has resulted in various advances in diagnosis and treatment. The most common pathogens of CAP include Streptococcus pneumoniae, Haemophilus influenzae, and atypical pathogens; however, the underlying pathogen often is unknown. Treatment of CAP has evolved because of changing etiologic patterns and increasing antimicrobial resistance among common respiratory pathogens. Among the groups that have established treatment guidelines for CAP are the American Thoracic Society (ATS), the Infectious Diseases Society of America (IDSA), and the Centers for Disease Control and Prevention (CDC). These guidelines establish risk factors associated with drug resistance or infection with specific pathogens. In addition, each guideline provides unique recommendations that are similar in some ways, yet different in others. By understanding the various risk factors for drug resistance and the treatment options endorsed by these guidelines, physicians can treat patients with the most appropriate antimicrobial available.

Acute upper viral respiratory infection (VRI) is the number one cause of illness for which patients seek medical care in the United States. Rhinoviruses, members of the family Picornaviridae, are the causative pathogens in more than half of VRIs, and they are associated with acute exacerbations of respiratory disease, including asthma, sinusitis, otitis media, and COPD. Owing to the lack of commercial availability of rapid and cost-effective laboratory tests to confirm the presence of VRI, the diagnosis is most commonly made empirically, based on patient history and physical examination. Currently, no antiviral agents that are active against picornaviruses are available for clinical use. Antimicrobial agents, frequently prescribed for VRIs, are not active against viruses, and their inappropriate and widespread use has contributed to an increase in antimicrobial resistance among bacteria commonly involved in respiratory tract infections. Several newer antiviral agents are being evaluated for treatment of VRIs. Although a variety of mechanisms and agents have been tested, few have shown significant clinical benefit in human trials. The most advanced antiviral agent in clinical trials is pleconaril, a novel viral capsid–binding inhibitor with potent and highly specific in vitro activity against the majority of serotypes of rhinoviruses and enteroviruses. Clinical trials of pleconaril for the treatment of VRIs have been conducted, and the role of pleconaril in patients with chronic lung disease is being evaluated.

CAP in elderly patients carries a significant economic and clinical burden and will be more commonly encountered in the future as the US population ages. Diagnosis may be obscured by a nonclassic presentation in an elderly patient, and the clinician needs to be especially suspicious of pneumonia whenever the clinical status of an elderly patient deteriorates. The single most important clinical decision is the site of care; this determination is not always based on clinical factors but also on social factors. Severity assessment is key to stratifying appropriate therapy and to predicting outcome. Timely and appropriate empiric therapy enhances the likelihood of a good clinical outcome, although clinical resolution may be more delayed than in younger patients. Newly emerging patterns of antibiotic resistance have altered recent guidelines for CAP treatment; DRSP is now a consideration in elderly patients because an age older than 65 years is a well-described risk factor for infection with this organism. Prevention should always be implemented, with a focus on pneumococcal and influenza vaccination.

Nosocomial pneumonia is the second most frequent nosocomial infection and represents the leading cause of death from infections that are acquired in the hospital. In the last decade, a large body of data has accumulated that points to the substantial impact of inadequate antibiotic treatment as a major risk factor for infection-attributed mortality in ventilator-associated pneumonia (VAP) patients. In most instances, high-risk pathogens (eg, highly resistant Gram-negative bacilli, such as Pseudomonas aeruginosa and Acinetobacter spp, as well as methicillin-resistant staphylococci) are the predominant microorganisms causing excess mortality. Among various risk factors for mortality from VAP, which include the severity of the underlying disease and the degree of functional physiologic impairment caused by the pulmonary infectious process, only inappropriate antibiotic therapy is directly amenable to modification by clinicians. Secondary modifications of an initially failing antibiotic regimen do not substantially improve the outcome for these critically ill patients. Therefore, the best approach for reducing infection-related mortality seems to be the initial institution of an adequate and broad-spectrum antibiotic regimen in severely ill patients, which should be modified in a de-escalating strategy when the results from microbiologic testing become available. To circumvent the inherent danger of the emergence of resistance in ICU patients, additional measures have to be implemented and tested in clinical trials to reduce antibiotic consumption, shorten the duration of antibiotic treatment, and reduce the selection pressure on the ICU flora. This latter goal could be met by new antibiotic strategies including scheduled changes of recommended empiric antibiotic regimens at fixed intervals on a rotating basis.

Study objective: To conduct a cost-effectiveness analysis of IV-to-oral regimens of azithromycin vs cefuroxime with or without erythromycin in the treatment of patients hospitalized with community-acquired pneumonia (CAP). Patients: Of the 268 evaluable patients enrolled into a randomized, multicenter clinical trial of adults, 266 patients had sufficient data to be included in this cost-effectiveness analysis. One hundred thirty-six patients received azithromycin, and 130 patients received cefuroxime with or without erythromycin. Methods: A pharmacoeconomic analysis from the hospital provider perspective was conducted. Health-care resource utilization was extracted from the clinical database and converted to national reference costs. Decision analysis was used to structure and characterize outcomes. Sensitivity analyses were performed, and statistics were applied to the cost-effectiveness ratios. Results: The clinical success and adverse event rates and antibiotic-related length of stay were 78%, 11.8%, and 5.8 days for the azithromycin group and 75%, 20.7%, and 6.4 days for the group receiving cefuroxime with or without erythromycin, respectively. Geometric mean treatment costs were $4,104 (95% confidence interval [CI], $3,874 to $4,334) for the azithromycin group, and $4,578 (95% CI, $4,319 to $4,837) for the group receiving cefuroxime with or without erythromycin (p 0.06). The cost-effectiveness ratios were $5,265 per expected cure for the azithromycin group, and $6,145 per expected cure for group receiving cefuroxime with or without erythromycin (p 0.05). Conclusions: Despite a higher per-dose purchase price, overall costs with azithromycin tended to be lower due to decreased duration of therapy, lower preparation and administration costs, and reduced hospital length of stay. As empiric therapy, azithromycin monotherapy was cost-effective compared to cefuroxime with or without erythromycin for patients hospitalized with CAP who have no underlying cardiopulmonary disease, and no risk factors for either drug-resistant pneumococci or enteric Gram-negative pathogens. (CHEST 2002; 122:1271–1279)

Study objectives We evaluated the role of sputum examination in the management of patients with community-acquired pneumonia (CAP) in a primary-care hospital without microbiologic laboratory facilities. Design and interventions A diagnostic strategy using regular collection of sputum samples, Gram staining in a local laboratory, and mailing of samples to a commercial laboratory for culture analysis. Setting A 200-bed primary-care hospital without subspeciality physicians. Patients One hundred sixteen consecutive patients with a diagnosis of CAP were prospectively evaluated during a 12-month period. Results Of 116 patients, 42 patients (36%) were capable of producing a sputum sample. Age ≥ 75 years (odds ratio [OR], 0.4; 95% confidence interval [CI], 0.18 to 0.93) and prior ambulatory antimicrobial treatment (OR, 3.2; 95% CI, 1.2 to 8.4) were independent predictors of sputum production. A delay in collection and processing of sputum samples of > 24 h was present in 31% and 39%, respectively. A delay in collection yielded an increased number of Gram-negative enteric bacilli and nonfermenters (44% vs 7%, p = 0.056). A delay in processing was associated with an increased number of Candida spp isolates (33% vs 9%, p = 0.16). The overall diagnostic yield was low (10 of 116 patients, 9%) due to a limited number of valid samples (n = 23 of 42 patients, 55%) and a limited number of definitely or probably positive samples on Gram's stain and culture (n = 10 of 42 patients, 24%). Prior ambulatory antimicrobial treatment was associated with a reduction in diagnostic yield (14% vs 56%, p = 0.09). The impact of diagnostic results on antimicrobial treatment decisions was minimal, with antimicrobial treatment directed to diagnostic results in only one patient. Conclusions We conclude that in this setting representative of primary-care hospitals in Germany, sputum had a low diagnostic yield and did not contribute significantly to patient management.

Numerous guidelines for CAP have been developed, and although each is different, many principles are common to all recommendations. A guideline should focus on a wide range of issues surrounding the delivery of care, including advice about when to admit patients to the hospital or ICU; which antibiotic regimens to select for specific patient populations; which pathogens to target in empiric therapy; which diagnostic tests to order; how to assess the importance of specific causative pathogens, such as drug-resistant pneumococci, atypical pathogens, and gram-negative pathogens; how to evaluate the response to therapy and when to switch responding patients to oral therapy; and how to prevent CAP effectively through appropriate use of immunization against pneumococcus and influenza. Currently, many new antibiotic choices have emerged in the macrolide, quinolone, beta-lactam, ketolide, and oxazolidinone classes, and specific issues surrounding selection of these agents must be considered. All of the available data can be synthesized into a disease management guideline, and current therapy in the United States generally is consistent with existing recommendations. This consistency not only has led to more uniformity in patient care, but also has led to measurable benefits in patient outcomes, including reduced mortality for hospitalized patients with CAP. Guidelines not only are a useful tool for managing patients with CAP, but also they serve the purpose of defining current issues in patient care and stimulating the search for new tools and management approaches for this important clinical problem.

Study objective: To determine the cost-effectiveness of sequential IV to oral gatifloxacin therapy vs IV ceftriaxone with or without IV erythromycin to oral clarithromycin therapy to treat community-acquired pneumonia (CAP) patients requiring hospitalization. Patients: Two hundred eighty-three patients enrolled in a randomized, double-blind, clinical trial were eligible for inclusion in the cost-effectiveness analysis. Methods: Data collected included patient demographics, clinical and microbiological outcomes, length of stay (LOS), and antibiotic-related LOS (LOSAR). Costs evaluated include drug acquisition (level 1); plus costs of preparation, dispensing, and administration, treating adverse events, and clinical failures (level 2); plus hospital per diem costs (level 3). Robustness of economic findings was tested using sensitivity analyses. Results: Two hundred three patients were clinically and economically evaluable (98 receiving gatifloxacin and 105 receiving ceftriaxone). IV erythromycin was administered to 35 patients in the ceftriaxone-treated group. Oral conversion was achieved in 98% of patients in each group. Clinical cure and microbiological eradication rates did not differ statistically (98% and 97% with gatifloxacin vs 92% and 92% with ceftriaxone, respectively). Overall, neither geometric mean LOS nor LOSAR differed significantly (4.2 days and 4.1 days with gatifloxacin vs 4.9 days and 4.9 days with ceftriaxone, respectively). Treatment failures in the ceftriaxone group contributed to a mean incremental increase in LOSAR of 1.09 days and increased mean cost per patient. The geometric mean costs per patient (level 3) were $5,109 for gatifloxacin and $6,164 for ceftriaxone (p = 0.011). The cost-effectiveness ratios (mean cost per expected success) were $5,236:1 and $7,047:1 for gatifloxacin and ceftriaxone, respectively. Conclusions: Gatifloxacin monotherapy for CAP patients requiring hospitalization is clinically effective and provides an economic advantage compared to the regimen of ceftriaxone with or without erythromycin IV with a switch to oral clarithromycin.

Hospital-acquired pneumonia (HAP) is a serious cause of morbidity and mortality. It is the second leading cause of nosocomial infection in the United States and the one with the highest rate of mortality. 6,26 Hospital-acquired pneumonia is defined as any pneumonia occurring after the third day of hospitalization 6 ; that is, more than 48 to 72 hours after admission, exclusive of any pneumonia that may be incubating at the time of admission. The diagnostic criteria for nosocomial pneumonia require that the patient have an examination showing rales, dullness to percussion, or an infiltrate on chest radiograph, accompanied by at least one of the following: purulent sputum, isolation of a pathogen (from respiratory samples or blood culture), or histopathologic evidence of pneumonia. Ventilator-associated pneumonia (VAP) is a variant of HAP and is defined as bacterial pneumonia arising in any patient who has been mechanically ventilated for at least 48 hours. Criteria for definite and probable VAP have been developed (table 1), and the definition is designed to eliminate pneumonia that is incubating at the time of intubation. In the intensive care unit (ICU), most (>85%) pneumonias are associated with mechanical ventilation 6,18,70 and are generally VAPs. In the ICU, many patients on mechanical ventilation require tracheostomy, and many of these patients develop pneumonia, but the pathogenesis, epidemiology, and clinical significance of respiratory infection in this population may be different from those seen in the endotracheally intubated patient. In this review, the authors focus on the problems associated with VAP, with a particular emphasis on the patient on long-term ventilation with tracheostomy who is recovering from acute (often on top of chronic) illness.

Use of nucleic acid amplification techniques has increased the identification of respiratory viruses (RVs) in adult patients with community-acquired pneumonia (CAP). The objectives of the present study were to identify RV in patients with CAP using three different sampling methods and to compare CAP virus proportions and types with two comparison groups.The study population included 183 adult patients with CAP, 450 control subjects, and 201 patients with nonpneumonic lower respiratory tract infection (NPLRTI). Each participant was sampled by oropharyngeal swab, nasopharyngeal swab, and nasopharyngeal washing, and the samples were tested for detection of 12 RVs by multiplex TaqMan Hydrolysis probe-based real-time polymerase chain reaction (Integrated DNA Technology; Coralville, IA).At least one RV was identified in 58 patients with CAP (31.7%) compared with 32 (7.1%) in control subjects and 104 (51.7%) in patients with NPLRTI (P.01 and P.01, respectively). Coronaviruses were identified in 24 (13.1%) patients with CAP, compared with 17 (3.8%) in control subjects, and 21 (10.4%) patients with NPLRTI. Respiratory syncytial virus was identified in 13 (7.1%), four (0.9%), and seven (3.5%); rhinovirus in nine (4.9%), nine (2.0%), and 15 (7.5%); and influenza virus in eight (4.4%), two (0.4%), and 63 (31.3%) patients with CAP, control subjects, and patients with NPLRTI, respectively.The proportion of RV involvement in CAP is higher than previously reported. The proportion of RV identified in healthy subjects is significantly lower than in CAP, but it is not zero and should be weighed when interpreting corresponding proportions among patients.

The role of infection in exacerbations of COPD remains controversial and incompletely understood. Although some investigators believe that bacteria are not important for patients with exacerbation, we disagree and believe that patients with at least two of the three cardinal symptoms of exacerbation should receive antibiotic therapy. With an open-minded view of the area, we review the data, showing that bacteriologic studies, pathologic investigations, and clinical trials all support roles for bacteria and antibiotic therapy in this disease. Still, many questions remain, and future studies will be needed to better define the mechanisms of bacterial invasion in the bronchitic patient and to develop effective vaccines to prevent exacerbations. In the meantime, we must rely on antibiotic therapy, and we will need prospective studies to corroborate preliminary findings showing that different patients may require different therapies; thus, patient subsetting may be vital in the selection of antibiotic therapy for exacerbations of COPD.

F ew investigators have studied the role of bronchoscopy in evaluating and managing patients with nosocomial pneumonia who are not responding to initial antibiotic therapy. This discussion examines whether the information provided by bronchoscopy has value in this setting, as well as whether the concept of using bronchoscopy for the nonresponding patient is a logical one. Importantly, serial bronchoscopy is generally performed while the patient is receiving antibiotic therapy. Such therapy can reduce the yield and accuracy of quantitative cultures of respiratory secretions. The presumption for using serial cultures in the nonresponding patient is that bacteria are present that have not been eliminated by currently administered antibiotics. Moreover, these organisms can be identified early enough so that changes in therapy will improve the outcome in these patients.

Objectives To determine the effect of age, severity of lung disease, severity and frequency of exacerbation, steroid use, choice of an antibiotic, and the presence of comorbidity on the outcome of treatment for an acute exacerbation of COPD. Design A retrospective chart analysis over 24 months. Setting A university Veterans Affairs medical center. Patients Outpatients with COPD who were treated with an antibiotic over a period of 24 months for an acute exacerbation of COPD. Methods Severity of an acute exacerbation of COPD was defined using the criteria of Anthonisen et al: increased dyspnea, increased sputum volume, and increased sputum purulence. Severity of lung disease was stratified based on FEV 1 percent predicted using American Thoracic Society guidelines (stage I, FEV 1 ≥ 50%; stage II, FEV 1 35 to 49%; stage III, FEV 1 Results One-hundred seven patients with COPD (mean age ± SD, 66.9 ± 9.5 years) experienced 232 exacerbations over 24 months. First-line antibiotics (trimethoprim-sulfamethoxazole, ampicillin/amoxicillin, and erythromycin) were used to treat 78% of all exacerbations. Treatment failure was noted in 12.1% of first exacerbations and 14.7% of all exacerbations, with more than half the failures requiring hospitalization. Host factors that were independently associated with treatment failure included the following: FEV 1 Conclusion The results of our study suggest that patient host factors and not antibiotic choice may determine treatment outcome. Prospective studies in appropriately stratified patients are needed to validate these findings.

The role of antibiotics in acute exacerbations of chronic bronchitis (AECB) remains controversial because patients commonly harbor the same bacteria in their sputum at times of stability and at times of acute illness. However, prospective randomized controlled trials do show a benefit for the use of antibiotics, compared with placebo, in AECB, particularly if patients have at least 2 of the following 3 symptoms: increased dyspnea, increased sputum volume, increased sputum purulence. In this setting, antibiotics have value, leading to a more rapid resolution of symptoms and a more rapid return of peak flow rate, compared with placebo. In addition, antibiotics may prevent some patients from developing secondary pneumonia and may prolong the time between exacerbations. When antibiotics are used, a variety of factors must be considered in choosing an agent. These include the likelihood of antibiotic-resistant bacteria, a factor that relates to defining subsets of patients. Patients can fall into 1 of 3 categories, each with a different suggested therapy. These categories include simple AECB, complicated AECB, and AECB at risk for infection with P. aeruginosa. In addition, an antibiotic should be chosen with pharmacokinetics and pharmacodynamic behavior in mind. In the future, research will need to confirm that careful selection of specific agents for specific patients can lead to improved patient outcomes, but already some preliminary data are supporting this concept.

In 1994, the National Center for Health Statistics estimated that more than 14 million people (54 per thousand) had chronic bronchitis and sought treatment for 90.9% of their acute episodes. However, few studies have been done on the treatment cost of chronic bronchitis using national data. We conducted a retrospective analysis of claims for patients treated for acute exacerbations of chronic bronchitis (AECB) to assess the frequency of services rendered and the costs to the health care system. Records were selected for the study based on a primary diagnosis of AECB according to the International Classification of Diseases, Ninth Revision, code. Medicare was the primary source of data on patients agedor =65 years; data from the National Healthcare and Cost Utilization Project, the National Ambulatory Medical Care Survey, and the National Hospital Ambulatory Medical Care Survey were used for patients aged65 years. We calculated a total treatment cost of $1.2 billion for patients agedor =65 years and $419 million for patients aged65 years. These calculations were based on the following: 280,839 hospital discharges resulting in hospital costs of $1.1 billion for the 207,540 patients agedor =65 years, and $408 million for the 73,299 patients aged65 years. The mean hospital length of stay was 6.3 days with a mean cost of $5497 for patients agedor =65 years and 5.8 days with a mean cost of $5561 for younger patients. Room and board represented the largest percentage of the mean hospital costs of AECB. Inpatient physician services cost $32 million and $11 million for the 2 age groups, respectively. Diagnosis-specific data for outpatient services were found to be less reliable than inpatient data, possibly due to diagnostic coding omissions; 331,000 outpatient office visits for AECB were found for those agedor =65 years and 237,000 visits for those aged65 years, resulting in respective total outpatient costs of $24.9 million and $15.1 million. If the number of outpatient visits remain consistent with 1994 levels, there would be 5.8 million visits annually for those agedor =65 years and 4.2 million visits for those aged65 years; total outpatient costs would be $452 million and $317 million, respectively. Because the treatment costs of AECB are largely the costs of hospitalization, any new therapy that allows more patients to be treated in the outpatient setting is likely to generate significant savings.

Although controversial, antimicrobial therapy for the treatment of acute exacerbations of chronic bronchitis (AECB) appears beneficial in patients with a history of repeated infections, those who have comorbid illnesses, and those with marked airway obstruction. In a community-based, open, randomized trial, the efficacy and safety of ciprofloxacin (CIP) 750 mg and clarithromycin (CLA) 500 mg, each given twice daily for 10 days, were compared in 2180 patients with AECB (1083 CIP, 1097 CLA). Patients were >40 years of age and had complicated/severe AECB episodes defined as at least three episodes within the past year, at least three comorbid conditions, previous failed antibiotic treatment for AECB within the previous 2 to 4 weeks, or community susceptibility data indicating a high number of resistant pathogens. Significant bacterial isolates (>10(5) colony-forming units per milliliter) from homogenized sputa were identified. Susceptibility to a range of antimicrobials was determined by the microbroth dilution technique. The majority of patients were white (83%) and were current or previous smokers (81%). Mean patient age was 62 years. A history of at least three AECB episodes in the previous year was reported by 54% of CIP-treated patients and 53% of CLA-treated patients. Of 777 primary isolates positively identified and cultured from 673 patients, the bacterial pathogens isolated and their incidence included Haemophilus species, 28%; Moraxella catarrhalis, 18%; Enterobacteriaceae, 18%; Staphylococcus aureus, 17%; Streptococcus pneumoniae, 7%; and Pseudomonas aeruginosa, 4%. Beta-lactamase production was found in 38% of Haemophilus influenzae, 10% of Haemophilus parainfluenzae, and 85% of M catarrhalis isolates. Thirty-four percent of S pneumoniae isolates were resistant to penicillin (minimum inhibitory concentration > or =0.12 mg/L). Among the 673 patients who were valid for clinical assessment and had a pretherapy pathogen isolated, clinical success and overall bacteriologic eradication rates at the end of therapy were 93% and 98% for CIP versus 90% and 96% for CLA. The differences between CIP and CLA did not reach statistical significance. Superinfections were reported significantly more frequently in CLA-treated (3%) versus CIP-treated patients (1%). Eradication rates for specific organisms for CIP and CLA, respectively, were Haemophilus species, 99% and 93%; M catarrhalis, 99% and 100%; S pneumoniae, 91% and 92%; and Enterobacteriaceae, 100% and 95%. Drug-related adverse events occurred in 12% of CIP-treated patients and 10% of CLA-treated patients. CIP 750 mg b.i.d. had a higher (but not statistically significant) clinical and bacteriologic cure rate than CLA 500 mg b.i.d. in the treatment of patients with bacteriologically proven complicated/severe AECB. The causative bacterial pathogens of AECB appear to be evolving, with a predominance of gram-negative and other resistant organisms observed. Thus antibiotic therapy for at-risk patients with AECB should include agents that have activity against gram-negative pathogens.

Study objective In patients with severe COPD, acute infective exacerbations are frequent. Streptococcus pneumoniae and Haemophilus influenzae are the most commonly isolated bacteria in sputum cultures from these patients. We hypothesized that in patients with advanced disease, Gram-negative bacteria other than H influenzae play at least an equally important role. Methods We evaluated clinical data and sputum culture results from 211 unselected COPD patients admitted to our hospital with an acute infective exacerbation of COPD. One hundred twelve patients fulfilled our protocol criteria of reliable microbiologic results and reproducible lung function tests; the patients were categorized according to the recently published three stages of severity. Results Lung function tests revealed an FEV 1 of ≥50% of the predicted value in 30 patients (stage I), an FEV 1 of 35% to 1 of ≤35% of the predicted value in 34 patients (stage III). Bacteria were classified into three groups: group 1 contained S pneumoniae and other Gram-positive cocci; group 2, H influenzae and Moraxella catarrhalis ; and group 3, Enterobacteriaceae and Pseudomonas spp. For all patients together, the most frequently isolated bacteria were group 3 organisms (Enterobacteriaceae and Pseudomonas spp, 48.2%), followed by group 1 organisms (S pneumoniae and other Gram-positive cocci, 30.4%), and group 2 organisms ( H influenzae and M catarrhalis , 21.4%). In stage I patients, 14 of 30 had bacteria from group 1, seven of 30 had group 2, and nine of 30 had group 3. In stage II patients, eight of 30 had group 1 bacteria, 10 of 30 had group 2, and 12 of 30 had group 3. In stage III patients, 12 of 52 had group 1 bacteria, seven of 52 had group 2, and 22 of 52 had group 3. The three groups of bacteria causing infective exacerbations were unevenly distributed among the three severity stages of lung function (p=0.016). Conclusion There is a correlation between deterioration of lung function and the bacteria isolated from patients with infective exacerbations of COPD. In acute infective exacerbations, Enterobacteriaceae and Pseudomonas spp are the predominant bacteria in patients with an FEV 1

In a multicenter, community-based study involving more than 300 primary care physicians in the United States, the efficacy and safety of ciprofloxacin and clarithromycin were compared in the treatment of patients with complicated or severe acute bacterial exacerbations of chronic bronchitis (i.e., those who had failed previous antibiotic treatment within the prior 2 to 4 weeks; those with susceptibility data suggestive of a resistant pathogen; those having three or more acute exacerbations of chronic bronchitis [AECB] within the past year; and those having three or more comorbid conditions). Patients were randomized to either ciprofloxacin (CIP) 750 mg BID or clarithromycin (CLR) 500 mg BID, both administered for 10 days; all patients were treated on an outpatient basis. Clinical response at the end of therapy was the primary efficacy variable. An interim analysis was performed on the results from 743 patients (369 CIP, 374 CLR) with clinical and bacteriologic evidence of a bronchopulmonary infection who had completed an ongoing study as of the end of May 1997. Three hundred nine pathogens were isolated before therapy, including Haemophilus spp (75 isolates), Moraxella catarrhalis (67 isolates), Staphylococcus aureus (55 isolates), and Streptococcus pneumoniae (23 isolates). Seven hundred eighteen patients (97%) were included in the efficacy-valid population. Clinical success at the end of therapy was observed in 90% (272 of 302) and 88% (274 of 313) of efficacy-valid patients treated with CIP and CLR, respectively (95% confidence interval [CI] = -2.4 to 7.6). Corresponding rates for the intent-to-treat population were also 90% (283 of 314) and 88% (281 of 321), respectively (95% CI = -2.3 to 7.5). The bacteriologic response for efficacy-valid patients at the end of therapy was 98% (119 of 122) for CIP-treated and 93% (103 of 111) for CLR-treated patients (95% CI = -0.8 to 10.2). The eradication rates for the three most commonly isolated gram-negative pathogens were 100% for CIP-treated and 95% for CLR-treated patients and 96% each for the two most commonly isolated gram-positive organisms. Superinfections due to respiratory tract pathogens were more common in the CLR group (10 organisms) than in the CIP group (4 organisms). Seventy-four (20%) CIP-treated and 62 (17%) CLR-treated patients reported 118 and 103 respective study-emergent adverse events. Headache, abdominal pain, diarrhea, nausea, and vomiting in CIP-treated patients and diarrhea, nausea, vomiting, and taste perversion in CLR-treated patients were the most commonly reported adverse events. Treatment of patients with complicated or severe AECB with CIP 750 mg BID was associated with rates of clinical success and bacteriologic eradication similar to those with CLR.

Nosocomial pneumonia is a common and serious problem among hospitalized patients, particularly those treated with mechanical ventilation. This article discusses infection control, the role of respiratory therapy equipment and endotracheal tubes, mobilization of tracheobronchial secretions, the role of the gastrointestinal tract, nutritional support and the role of the stomach, prophylactic antibiotics, and immunomodulation. Although there are no proven modalities for immunoprophylaxis of nosocomial pneumonia, it is possible that early administration of a single agent or combination of immune modulators may prove effective in reducing the mortality associated with nosocomial pneumonia.

The elderly are more susceptible to pneumonia and more likely to die from this infection than younger populations. Older patients with pneumonia requiring hospitalization are more likely to develop complications necessitating longer hospital stays. This article focuses on features of common lower respiratory tract infections and physiologic and immunologic characteristics of elderly patients that might obscure classic clinical presentation of pneumonia. Treatment factors unique to elderly patients with severe pneumonia are also discussed.

Pneumonia is both more prevalent in the elderly and more severe. This article reviews the approach to nonresolving or slowly resolving pneumonia in the elderly. Specific attention will be given to the natural history of commonly occurring pneumonias in this age group, related host defense impairments, unusual infectious causes of slowly resolving pneumonia, and noninfectious mimics of pneumonia.

By nature, nosocomial infections in general, and pneumonia specifically, are opportunistic, preying on patients who are already seriously ill. These infections are a major source of morbidity and mortality for these individuals. Among the elderly, pneumonia is more common and more likely to lead to death. The author reviews the epidemiology and risk factors for nosocomial pneumonia among the elderly.