Joshua P. Metlay

Impact of Penicillin Susceptibility on Medical Outcomes for Adult Patients with Bacteremic Pneumococcal Pneumonia

The impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia was evaluated in a retrospective cohort study conducted during population-based surveillance for invasive pneumococcal disease in the greater Atlanta region during 1994. Of the 192 study patients, 44 (23%) were infected with pneumococcal strains that demonstrated some degree of penicillin nonsusceptibility. Compared with patients infected with penicillin-susceptible pneumococcal strains, patients whose isolates were nonsusceptible had a significantly greater risk of in-hospital death due to pneumonia (relative risk [RR], 2.1; 95% confidence interval [CI], 1-4.3) and suppurative complications of infection (RR, 4.5; 95% CI, 1-19.3), although only risk of suppurative complications remained statistically significant after adjustment for baseline differences in severity of illness. Among adults with bacteremic pneumococcal pneumonia, infection with penicillin-nonsusceptible pneumococci is associated with an increased risk of adverse outcome.

Prevalence of Inappropriate Antibiotic Prescriptions Among US Ambulatory Care Visits, 2010-2011

IMPORTANCE The National Action Plan for Combating Antibiotic-Resistant Bacteria set a goal of reducing inappropriate outpatient antibiotic use by 50% by 2020, but the extent of inappropriate outpatient antibiotic use is unknown. OBJECTIVE To estimate the rates of outpatient oral antibiotic prescribing by age and diagnosis, and the estimated portions of antibiotic use that may be inappropriate in adults and children in the United States. DESIGN, SETTING, AND PARTICIPANTS Using the 2010-2011 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, annual numbers and population-adjusted rates with 95% confidence intervals of ambulatory visits with oral antibiotic prescriptions by age, region, and diagnosis in the United States were estimated. EXPOSURES Ambulatory care visits. MAIN OUTCOMES AND MEASURES Based on national guidelines and regional variation in prescribing, diagnosis-specific prevalence and rates of total and appropriate antibiotic prescriptions were determined. These rates were combined to calculate an estimate of the appropriate annual rate of antibiotic prescriptions per 1000 population. RESULTS Of the 184,032 sampled visits, 12.6% of visits (95% CI, 12.0%-13.3%) resulted in antibiotic prescriptions. Sinusitis was the single diagnosis associated with the most antibiotic prescriptions per 1000 population (56 antibiotic prescriptions [95% CI, 48-64]), followed by suppurative otitis media (47 antibiotic prescriptions [95% CI, 41-54]), and pharyngitis (43 antibiotic prescriptions [95% CI, 38-49]). Collectively, acute respiratory conditions per 1000 population led to 221 antibiotic prescriptions (95% CI, 198-245) annually, but only 111 antibiotic prescriptions were estimated to be appropriate for these conditions. Per 1000 population, among all conditions and ages combined in 2010-2011, an estimated 506 antibiotic prescriptions (95% CI, 458-554) were written annually, and, of these, 353 antibiotic prescriptions were estimated to be appropriate antibiotic prescriptions. CONCLUSIONS AND RELEVANCE In the United States in 2010-2011, there was an estimated annual antibiotic prescription rate per 1000 population of 506, but only an estimated 353 antibiotic prescriptions were likely appropriate, supporting the need for establishing a goal for outpatient antibiotic stewardship.

Testing Strategies in the Initial Management of Patients with Community-Acquired Pneumonia

The clinician is faced with diagnostic and prognostic challenges in the initial management of patients with suspected community-acquired pneumonia. Each challenge corresponds to a specific management decision. The diagnostic question Does this patient have community-acquired pneumonia? corresponds to the decision on whether to treat with antimicrobial drugs. While other acute cough illnesses, such as acute exacerbations of chronic bronchitis and sinusitis, are antibiotic responsive, community-acquired pneumonia is the only acute respiratory tract infection in which delayed antibiotic therapy has been associated with increased risk for death (1). This emphasizes the importance of prompt, accurate diagnosis. The prognostic question Does this patient with community-acquired pneumonia have a high severity of illness? corresponds to decisions regarding the intensity of management. These decisions, including the need for parenteral therapy and supportive care, ultimately relate to the decision on whether to hospitalize the patient. Accordingly, we review the test characteristics of the history, physical examination, and laboratory findings in diagnosing community-acquired pneumonia and predicting short-term risk for death from the infection. We review the literature and summarize the test characteristics of individual diagnostic and prognostic factors, as well as groups of factors in diagnostic or prognostic rules. Finally, we consider the implications of these test characteristics from the perspective of decision thresholds that reflect the balance of the costs and harms of false-positive and false-negative information against the benefits of true-positive and true-negative information. This review does not consider the accuracy of clinical and laboratory findings in determining the cause of community-acquired pneumonia. Recent guidelines for the treatment of patients with community-acquired pneumonia summarize the limited value of testing to determine cause in many clinical settings and emphasize the importance of empirical guidelines to aid antibiotic selection, primarily on the basis of illness severity (2, 3). Methods This paper is expanded from two previous systematic reviews of the diagnosis (4) and prognosis (5) of community-acquired pneumonia (5). We updated our publication database by including updated search strategies from MEDLINE from January 1996 through December 2000 (search strategies available upon request) and reviewing the references from all retrieved new articles. Articles on the Diagnosis of Community-Acquired Pneumonia We emphasized studies with consecutive series of patients suspected of having pneumonia who had a chest radiograph regardless of the results of diagnostic testing and had it interpreted without knowledge of the other clinical findings (6). We excluded articles that did not report findings for patients with and without pneumonia. We excluded studies of children and inpatients and studies that did not obtain chest radiographs in all patients suspected of having community-acquired pneumonia. We abstracted the total number of persons studied and the number of true-positive, true-negative, false-positive, and false-negative results for each diagnostic test, using the results of chest radiography as the gold standard. Because of the heterogeneity in study designs, we did not pool data. Instead, we calculated positive and negative likelihoods for each finding in each study. We report the range of likelihood ratios only for findings that were statistically significantly (P < 0.05) associated with the presence or absence of pneumonia in two or more studies. Positive likelihood ratios equal the probability of a positive test result in patients with disease divided by the probability of a positive result in patients without disease. Negative likelihood ratios equal the probability of a negative test result in patients with disease divided by the probability of a negative result in patients without disease. Likelihood ratios represent the degree to which positive results raise the pretest probability of disease and negative results lower the pretest probability of disease. Likelihood ratios greater than 5 or less than 0.2 generate moderate to large shifts in disease probability; likelihood ratios of 2 to 5 and 0.5 to 0.2 generate small changes in probability; and likelihood ratios of 1 to 2 and 0.5 to 1 generate rarely important changes in probability (7). Articles on the Prognosis of Community-Acquired Pneumonia We included studies only if radiographic confirmation of pneumonia was an inclusion criterion. We excluded studies of nosocomial pneumonia, nursing homeacquired pneumonia, noninfectious pneumonia, pediatric pneumonia, and pneumonia in patients with HIV infection. The cause, treatment, and prognosis of these different types of pneumonia are substantially different from those in community-acquired pneumonia in adults. We also excluded articles with small case series (<25 participants), review articles without original data, and trials of antibiotic efficacy. Finally, we excluded articles that did not report the data in a form that permitted calculation of summary odds ratios (ORs) for the risk factors. We collected the number of deaths of patients with and without each factor, limiting ourselves to factors reported in at least two independent publications. We used summary ORs and their associated 95% CIs to quantify the risk for death associated with each prognostic factor, combining ORs by the MantelHaenszel method (8, 9). Diagnosis of Pneumonia Community-acquired pneumonia is defined as an acute infection of the lung parenchyma accompanied by symptoms of acute illness. Patients who acquire the infection in hospitals or long-term care facilities are typically excluded from the definition (2). The gold standard for diagnosing community-acquired pneumonia should be the identification of a microbiological pathogen isolated directly from the lung tissue. However, such a test (for example, lung puncture or biopsy) is rarely undertaken for the routine diagnosis of community-acquired pneumonia. An alternative gold standard could be based on a combination of clinical symptoms; radiographic, laboratory, and microbiological findings; and clinical response to antimicrobial therapy. However, in both clinical and research settings, isolated findings on chest radiography are often interpreted as the gold standard for the initial diagnosis of pneumonia even though chest radiography is neither 100% sensitive nor 100% specific for this condition. In terms of sensitivity, pneumonia can be present in the absence of an infiltrate on chest radiography at the time of diagnosis. However, the occurrence of this phenomenon has only limited support in the published literature. In an independent, blinded comparison of chest radiography with high-resolution computed tomography, chest radiography missed 8 of 26 (31%) cases of possible pneumonia that were identified on high-resolution computed tomography as any opacification or consolidation compatible with acute-phase lung involvement (10). While many of these missed cases had clinical and laboratory evidence of acute infection, it is not correct to assume that the sensitivity of chest radiography is as low as 69%, because these additional cases were not validated as true cases of community-acquired pneumonia based on microbiological evidence or response to antibiotic therapy. Dehydration may play an important role in the occurrence of pneumonia without findings on chest radiography (11), and a recent study suggests that patients with signs of dehydration on admission are more likely to have worsening chest radiographs over several days compared with patients without these signs (12). Thus, chest radiography is an imperfect gold standard test. The effect of these test characteristics on the decision to perform chest radiography depends on the pretest probabilities of the infection and the relative costs of over- and underdiagnosis of this infection. In the next section, we consider the effect of history and physical examination findings on the pretest probability of community-acquired pneumonia. Prevalence of Pneumonia in Patients The probability of pneumonia before the ordering of additional diagnostic testing depends on the clinical setting and the results of the medical history and physical examination. We examine the influence of each factor independently and then in combination. Clinical Setting The prevalence of pneumonia in patient populations presenting with acute respiratory illnesses varies substantially across study samples. In one study that examined consecutive patients with acute respiratory symptoms presenting to emergency departments and outpatient medical clinics, the prevalence of radiographically confirmed pneumonia was 7% (13). In a study examining patients with acute cough presenting to a military emergency department, the prevalence was only 2.6% (14). Recently, a prospective study of previously well adults (that is, no history of chronic lung or heart disease) with acute cough illness presenting to general practitioners in the United Kingdom found that 6% of patients met criteria for radiographic pneumonia (15). In contrast, in a recent study of patients presenting to a Veterans Affairs hospital with acute cough and change in sputum, 24 of 52 patients (46%) had chest radiographs consistent with pneumonia (16). However, this study included a nonconsecutive sample of predominately older male patients with underlying pulmonary and cardiac diseases. In our review of data from the National Ambulatory Medical Care Survey for 1980 to 1994, pneumonia was diagnosed in 4.7% of patients with acute cough who visited a primary care provider (17). Medical History Symptoms at presentation distinguish poorly between community-acquired pneumonia and other causes of respiratory illnesses. The likelihood ratio for these findings is typically close to 1.0 (

Healthcare utilization and cost of pneumococcal disease in the United States

BACKGROUND Streptococcus pneumoniae continues to cause a variety of common clinical syndromes, despite vaccination programs for both adults and children. The total U.S. burden of pneumococcal disease is unknown. METHODS We constructed a decision tree-based model to estimate U.S. healthcare utilization and costs of pneumococcal disease in 2004. Data were obtained from the 2004-2005 National (Hospital) Ambulatory Medical Care Surveys (outpatient visits, antibiotics) and the National Hospital Discharge Survey (hospitalization rates), and CDC surveillance data. Other assumptions regarding the incidence of each syndrome due to pneumococcus, expected health outcomes, and healthcare utilization were derived from literature and expert opinion. Healthcare and time costs used 2007 dollars. RESULTS We estimate that, in 2004, pneumococcal disease caused 4.0 million illness episodes, 22,000 deaths, 445,000 hospitalizations, 774,000 emergency department visits, 5.0 million outpatient visits, and 4.1 million outpatient antibiotic prescriptions. Direct medical costs totaled

Control of the Immune Response at the Level of Antigen-Presenting Cells: A Comparison of the Function of Dendritic Cells and B Lymphocytes

3.5 billion. Pneumonia (866,000 cases) accounted for 22% of all cases and 72% of pneumococcal costs. In contrast, acute otitis media and sinusitis (1.5 million cases each) comprised 75% of cases but only 16% of direct medical costs. Patients ≥ 65 years old, accounted for most serious cases and the majority of direct medical costs (

Educational interventions to improve antibiotic use in the community: report from the International Forum on Antibiotic Resistance (IFAR) colloquium, 2002.

1.8 billion in healthcare costs annually). In this age group, pneumonia caused 242,000 hospitalizations, 1.4 million hospital days, 194,000 emergency department visits, 374,000 outpatient visits, and 16,000 deaths. However, if work loss and productivity are considered, the cost of pneumococcal disease among younger working adults (18-<50) nearly equaled those ≥ 65. CONCLUSIONS Pneumococcal disease remains a substantial cause of morbidity and mortality even in the era of routine pediatric and adult vaccination. Continued efforts are warranted to reduce serious pneumococcal disease, especially adult pneumonia.

Surveillance for Second Primary Colorectal Cancer after Adjuvant Chemotherapy: An Analysis of Intergroup 0089

Publisher Summary This chapter discusses three areas where there have been recent advances of the immune response control. The first is that dendritic cells and B lymphocytes differ considerably in terms of their tissue distribution in situ and their surface properties. The relevance of these differences to APC function will be considered. The second is that each cell has distinct effects when tested for APC function in vitro and in situ . Presentation of soluble proteins, MHC and Mls antigens, viral antigens, and T cell-dependent antigens for antibody formation is each dealt with separately. The evidence that both B cells and dendritic cells regulate their APC function depending on their tissue localization and exposure to antigen and cytokines will be stressed. The third area relates to the mechanism of APC function, which includes how each APC processes antigen, acquires antigen in vivo , and forms stable contacts with responsive T cells. The dendritic cell family begins with a bone marrow precursor that likely seeds most non-lymphoid tissues. Following deposition of antigen, nonlymphoid dendritic cells may be mobilized to present antigen locally, or to migrate with that antigen via the blood and lymph to the T cell areas of lymphoid organs. Except for the bone marrow precursor, dendritic cells in all tissues from which they have been isolated are potent antigen-presenting cells (APCs) for a variety of T cell-dependent immune responses. In an analogous sense, B lymphocytes also encompass a diverse array of developmental stages, each with distinct functional properties. The immune system contains two diverse groups of cells, both of which can present antigens to T cells.

Dendritic Cells as Antigen Presenting Cells in Vivo

National and international strategies for the control of antibiotic resistance recommend education for health-care professionals and the public to promote prudent antibiotic use. This paper, based on discussions at the 2002 colloquium of the International Forum on Antibiotic Resistance (IFAR), provides an international discourse between theoretical approaches to behaviour change and practical experience gained in large-scale antibiotic use educational campaigns. Interventions are more likely to be effective if their aim is to change behaviour, rather than provide information. They should target all relevant groups, especially parents, children, day-care staff, and health-care professionals. They should use clear and consistent messages concerning bacterial versus viral infection, prudent antibiotic use, symptomatic treatment, and infection-control measures (eg, handwashing). Campaigns should use a range of communications using pilot-testing, strong branding, and sociocultural adaptation. Prime-time television is likely to be the most effective public medium, while academic detailing is especially useful for health-care professionals. Multifaceted interventions can improve antibiotic prescribing to some degree. However, there are few data on their effects on resistance patterns and patient outcomes, and on their cost-effectiveness. Current research aims include the application of behaviour-change models, the development and validation of prudent antibiotic prescribing standards, and the refinement of tools to assess educational interventions.

Association between Fluoroquinolone Resistance and Mortality in Escherichia coli and Klebsiella pneumoniae Infections: The Role of Inadequate Empirical Antimicrobial Therapy

Context Patients who have had colorectal cancer can develop second primary colorectal cancer. The American Cancer Society recommends that surveillance colonoscopy be performed 1 year after surgery, then every 3 to 5 years if results are negative. This surveillance strategy is unproven. Contribution This study documented an incidence rate of 274 cases of second primary colon cancer per 100 000 person-years after surgery with curative intent and 5-fluorouracil-based chemotherapy. The incidence of second cancer was higher than the incidence of first colorectal cancer in the general population, despite surveillance. Cautions This study suggests that surveillance may need to be more vigilant than currently recommended. However, more data are needed to decide how often to do surveillance colonoscopy. The Editors Colorectal cancer is a major public health problem, with more than 130 000 new cases thought to have occurred in the United States in 2001. Patients who have had colon cancer are at risk for second primary colon cancer, but the extent of this risk is unclear. The incidence and rate of development of second primary tumors have implications for appropriate surveillance of the colon after diagnosis of colorectal cancer. After first primary colon cancer is diagnosed, resection with curative intent is possible in approximately 75% of patients because the disease is limited to the bowel or to regional lymph nodes. The standard of care for patients with stage II or stage III disease is surgical resection, followed by adjuvant therapy for stage III disease. After surgery and adjuvant chemotherapy, patients frequently undergo some form of surveillance. Computed tomography of the abdomen, chest radiography, and measurement of carcinoembryonic antigen have been used to detect distant metastatic disease, although no convincing data show that these tests are cost-effective or improve survival (1). Colonoscopy or barium enema combined with flexible sigmoidoscopy has been used to survey for second primary colorectal cancer. Surveillance for second primary colorectal cancer serves two purposes: removal of premalignant polyps and early detection of malignancy. Most colorectal cancer is the product of slow, orderly progression from normal cells to malignancy. Surveillance with endoscopy and polypectomy has been shown to prevent colon cancer (2, 3). The most convincing data for this intervention come from the National Polyp Study, which found that in patients with adenomatous polyps, colonoscopic surveillance significantly decreased the incidence of colorectal carcinoma (3). The National Polyp Study also examined the question of how frequently to perform colonoscopic surveillance by comparing two surveillance strategies in patients who had recently had adenomas removed by colonoscopy (4). The study showed that repeated colonoscopy 3 years after colonoscopy and polypectomy in patients with adenomatous polyps was equivalent to more frequent surveillance. The authors conceded, however, that more frequent follow-up colonoscopy may be needed in patients with a history of colorectal cancer because they may have different biological characteristics and natural history. Current guidelines for surveillance of patients with a history of colon cancer are at least partially based on data from the National Polyp Study. The American Gastroenterological Association and the American Cancer Society recommend complete examination of the colon within 1 year of resection; if findings on this or on complete preoperative examination are normal, examination should be repeated in 3 years and then, if findings are again normal, every 5 years (5). In addition to finding new second primary tumors, surveillance within 1 year of colon cancer surgery may detect previously undetected polyps or synchronous tumors. Recent recommendations from the American Society of Clinical Oncology call for perioperative colonoscopy followed by colonoscopy every 3 to 5 years (1). However, deciding whether to extrapolate surveillance recommendations for patients with polyps to patients with a history of colon cancer requires a better understanding of the absolute and relative risk for second colorectal cancer in such patients. In the general population, the best estimates of the risk ratio for second primary colorectal cancer compared with first primary colorectal cancer have ranged from 1.5 to 3.0 (6, 7). The studies that have addressed this issue have had several deficiencies: incomplete follow-up, incomplete reporting of new cases, reporting of cumulative incidence rates (which do not consider length of follow-up), unknown surveillance practices in the study sample, arbitrary time cutoffs to distinguish new metachronous primary cancer from missed synchronous cancer, and heterogeneous patient samples (6-11). Thus, we do not know enough about the incidence of second primary colorectal cancer in patients with a history of colon cancer to devise optimal surveillance strategies. The purpose of our study was to estimate the incidence of second primary colon cancer in patients with a history of high-risk stage II or stage III colon cancer and to compare this incidence with that of first primary colon cancer in the general population and the National Polyp Study. Methods Patients Our study is a historical cohort analysis of patients who entered a trial of adjuvant therapy after surgery for colon cancer. This trial was designated Intergroup 0089 by the U.S. National Cancer Institute (12) and was approved by the Institutional Review Board of the University of Pennsylvania, Philadelphia, Pennsylvania. Patients with high-risk stage II or stage III cancer were randomly assigned to one of four 5-fluorouracil-based treatments. Patients were enrolled at 683 institutions, 73% of which were community-based medical centers. Surveillance guidelines for patients in the study included mandatory surveillance of the entire colon with colonoscopy or barium enema and flexible sigmoidoscopy at diagnosis, within 6 months of surgery, at 12 months, at 18 months, and then annually. At the discretion of each patients physician, surveillance could be done less frequently (every 18 to 24 months after the 6-month surveillance). Data Collection Patients were required to visit the treating oncologist at least every 3 months during the first year of the study and then every 6 months for 4 years. After 5 years, follow-up materials were collected annually until death. At each visit, data forms that included information on surveillance and documentation of second primary colorectal cancer were completed. Data on the diagnostic procedures used to diagnose the original colon cancer and on whether the entire colon was visualized at diagnosis were not always available, since these were not primary objectives of the protocol. Original data collection and statistical analysis were done by the Eastern Cooperative Oncology Group. Reference Groups We compared the observed incidence rate of second primary colorectal cancer in Intergroup 0089 with the rates of first primary colorectal cancer expected in two reference groups. The Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute monitors the incidence of colorectal cancer in 10 statewide registries (13). These data are routinely used as a surrogate for the average risk for colorectal cancer throughout the United States. We used age-, sex-, and ethnicity-specific rates for calendar years 1989 to 1993 since this period corresponded to the time during which patients were enrolled in Intergroup 0089. The National Polyp Study was a prospective study of 1418 patients who were referred for colonoscopy, during which one or more adenomas of the colon or rectum were removed (3, 4). The patients subsequently underwent periodic colonoscopy (randomly assigned to either years 1 and 3 or year 3 only) during an average follow-up of 5.9 years, and the incidence of colorectal cancer was ascertained. The incidence rate of colorectal cancer was compared with rates in three reference groups: two populations of patients with adenomatous polyps who did not have all polyps removed, and the SEER program. Five cases of invasive colorectal cancer were detected in a total of 8401 person-years of follow-up. The National Polyp Study found that colonoscopy with polypectomy decreased the incidence of colon cancer by approximately 90% compared with the other populations of high-risk patients and by 76% compared with the SEER population. Statistical Analysis In Intergroup 0089, the number of person-years at risk was calculated for each patient from the time of study entry until death, diagnosis of second primary colon cancer, or the last known time at which the patient was alive. Median time to second cancer and survival plots were calculated by using the Kaplan-Meier method. Incidence rates were defined as the total number of events divided by the total person-years of follow-up; 95% CIs were calculated by assuming a Poisson distribution. Our study primarily analyzed the diagnosis of second primary colorectal cancer. We established criteria to distinguish second primary cancer from an anastomotic recurrence or metastases. A tumor was classified as a second primary tumor if it was pathologically described as arising from a preexisting polyp or was found at a site distant from the original primary tumor (not at the site of the anastomosis), without evidence of penetration from the serosa of the bowel. Only tumors discovered after the original resection were considered second primary tumors, and only invasive cancer was included. In situ tumors were excluded because they were not included in either of our comparison groups and because, given the lack of potential for metastatic spread, they are of less clinical relevance. In our primary analysis, we did not specify a minimum time interval between treatment of the original primary tumor and detection of a second prim

Microbial Communities of the Upper Respiratory Tract and Otitis Media in Children

Antigen-presenting cells are of central importance for the generation and regulation of T cell-mediated immune responses. The specialized features of dendritic cells as antigen-presenting cells in selecting rare clones of antigen-specific T cells and activating them in vivo are described.