Richelle J. Cooper

Principles of Appropriate Antibiotic Use for Acute Pharyngitis in Adults: Background

1.0 Background Sore throat is one of the most common chief complaints of adults treated in an outpatient setting. Although its differential diagnosis is large and includes many other causes that are important to recognize (Table), the vast majority of immunocompetent adults presenting with sore throat have acute infectious pharyngitis. Most of the widespread antibiotic use in such patients is based on an effort to treat bacterial (particularly streptococcal) pharyngitis. Recognition and specific treatment of some of these other sore throat entities are important but are beyond the scope of this paper, which addresses the treatment of nongonococcal, nondiphtherial acute pharyngitis in healthy adults. Table. Differential Diagnosis of Sore Throat in the Immunocompetent Adult 1.1 Acute pharyngitis accounts for 1% to 2% of all visits to outpatient departments, physician offices, and emergency departments (1). A wide range of infectious agents, most commonly viruses, cause acute pharyngitis. Approximately 5% to 15% of cases in adults are caused by group A -hemolytic streptococcus (GABHS) (2-7). In some patients, it can be important to identify an infectious cause other than GABHS (for example, gonococcal pharyngitis, EpsteinBarr virus, and acute HIV infection), but in the vast majority of cases, acute pharyngitis in an otherwise healthy adult is self-limited and rarely produces significant sequelae. 1.2 Antibiotics are prescribed to a substantial majority (approximately 75%) of adult patients with acute pharyngitis (8). Physicians report that they prescribe unwarranted antibiotics because they believe that patients expect them, that patients will reconsult if antibiotics are not prescribed, that patients will be unsatisfied without a prescription, and that it is quicker to write a prescription than to explain why a prescription is not indicated (9-11). However, physicians are not very good at predicting which patients expect antibiotics (11, 12), and patient satisfaction depends less on whether an antibiotic is prescribed, or even whether preconsultation expectations are met, than on whether the physician shows concern and provides reassurance (9, 11-15). Delaying antibiotic prescriptions does not increase the chance that patients will return in the next few days for reconsultation. Prescribing antibiotics medicalizes the illness, and one study found increased likelihood that patients would return for the next similar illness (13, 15, 16). The inappropriate use of antibiotics can have significant negative consequences both to individual patients and to public health. Goals This paper examines the available evidence regarding the diagnosis and treatment of acute GABHS pharyngitis in adult patients. It makes recommendations that balance concerns about the potential consequences of untreated GABHS and the goal of decreasing inappropriate antibiotic prescriptions. It discusses pharyngitis in adults (patients 18 years of age), a population in which GABHS accounts for only approximately 5% to 15% of cases (2-7) and in which such complications as acute rheumatic fever are much less common. These guidelines do not apply to patients with a history of rheumatic fever, valvular heart disease, immunosuppression, or recurrent or chronic pharyngitis (symptoms > 7 days), or to patients whose sore throats have a cause other than acute infectious pharyngitis. They are not intended to apply during a known epidemic of acute rheumatic fever or streptococcal pharyngitis or in nonindustrialized countries in which the endemic rate of acute rheumatic fever is much higher than in the United States. Clinicians should always consider the epidemiologic circumstances when applying these recommendations in practice. Furthermore, these principles are not intended to comment on or contradict previous practice guidelines from other organizations (17, 18), which are primarily directed at sore throat evaluation in children. 2.0 Methods We conducted a systematic review of the literature from 1950 to 2000 for these evidence-based management principles. We identified all randomized, controlled trials or meta-analyses of randomized, controlled trials that contained clear definitions of criteria for inclusion, diagnosis, and outcomes, as well as studies evaluating diagnostic strategies for GABHS pharyngitis. We searched MEDLINE and the Cochrane Library, and we also searched the references of the inception articles to identify other studies. Our search strategy sought English-language articles and used the keywords sore throat, group A streptococcus, pharyngitis, tonsillitis, streptococcal pharyngitis, throat culture, and strep. Many of the identified articles had easily recognizable methodologic flaws (for example, use of convenience samples, exclusion of patients without a throat culture or those without a positive throat culture, and lack of an appropriate or clearly identified criterion standard), and we considered these limitations when evaluating the evidence and making our recommendations. Furthermore, the efficacy reported in the clinical trials may have been affected in part by repeated clinic visits, repeated cultures, and checks of patient adherence to pill ingestion, all of which would result in overestimation of the effect size of treatment. We did not mathematically summarize the various trials because of the variable quality of the cited evidence. 3.0 Evidence for Antibiotic Treatment of Pharyngitis Caused by GABHS Pharyngitis caused by GABHS is predominantly a disease of children 5 to 15 years of age. It has a prevalence of approximately 30% in pediatric pharyngitis but only 5% to 15% in adult pharyngitis in nonepidemic conditions (2-7, 19, 20). Physicians may consider prescribing antibiotics for streptococcal pharyngitis to prevent rheumatic fever, prevent acute glomerulonephritis, prevent suppurative complications, decrease contagion, and relieve symptoms. 3.1 Acute Rheumatic Fever Early randomized trials demonstrated that penicillin treatment of streptococcal pharyngitis is effective in preventing acute rheumatic fever (21-23) (relative risk, 0.28 [24]). This translated into a number needed to treat for benefit (NNTB) of approximately 63 to prevent one case of acute rheumatic fever in the samples studied. These early trials were usually performed in populations with a much higher incidence of acute rheumatic fever in both the treated and control groups than is present today. The reported incidence per population was approximately 60 times greater in 1965 than in 1994 (the last year for which the Centers for Disease Control and Prevention reported statistics); therefore, the NNTB today is undoubtedly much higher, in the range of approximately 3000 to 4000 (25-27). Carditis is the most serious complication associated with acute rheumatic fever. In recent outbreaks of acute rheumatic fever, carditis was seen in 50% to 91% of pediatric cases (28-31). These data probably reflect diagnosis of subclinical cases by echocardiography. Carditis occurred in approximately one third of adult cases of acute rheumatic fever (32, 33). The most important consequence of carditis, permanent valvular dysfunction, is most common after clinically severe carditis (28). Given that acute rheumatic fever is rare in adults, that carditis is not a common feature of adult cases of acute rheumatic fever, and that most cases of carditis in adults are mild or asymptomatic, the likelihood of permanent cardiac dysfunction seems to be very small. Thus, the NNTB to prevent a single case of clinically significant carditis is substantially greater than the NNTB to prevent a single case of acute rheumatic fever. During the 1980s, several outbreaks of acute rheumatic fever occurred, causing concern about reemergence of the disease (29-32, 34, 35). It is important to consider local epidemics. Physicians should be prepared to revise their treatment approaches if evidence suggests an outbreak. 3.2 Acute Glomerulonephritis Although poststreptococcal acute glomerulonephritis occurs, it is extremely rare, even in the absence of antibiotic treatment (36-41). Furthermore, no evidence shows that antibiotic therapy for pharyngitis decreases the incidence of this complication (36-41). 3.3 Peritonsillar Abscess The incidence of suppurative complications, regardless of treatment with antibiotics, is also low (42-45). A review of randomized trials from the 1950s and 1960s indicates that antibiotics decrease the incidence of peritonsillar abscess (quinsy) complicating streptococcal pharyngitis (24), with a best estimate for NNTB of 27. Modern clinical trials (44, 45) provide some evidence that targeting antibiotics to a subset of patients with higher clinical likelihood of GABHS may prevent peritonsillar abscess. However, in another recent review of GABHS pharyngitis in practice, Little and Williamson (46) reported that the risk for peritonsillar abscess was not reduced because many patients did not present for care until after the complication had developed (46). A recent retrospective study of more than 30 000 patients confirms these findings (47). Among patients who developed suppurative complications, 31 of 71 (44%) had them at first presentation (47). Of the other 56% who presented with pharyngitis before subsequent development of peritonsillar abscess, only approximately 25% showed GABHS on culture or rapid antigen test, and most (67%) had been treated with antibiotics that effectively eradicated GABHS. 3.4 Prevention of Spread of Disease Streptococcal infection often occurs in epidemics, and contagion is a problem in areas of overcrowding or close contact. Although treatment must continue for 10 days, 24 hours of antibiotic therapy greatly reduces the recovery of GABHS from pharyngeal cultures (41, 48-50). While antibiotics are recommended as a means of reducing spread in schools and other closed settings (20), the impact of treatment on disease spread in noninstitutionalized adult po

Principles of Appropriate Antibiotic Use for Treatment of acute respiratory Tract Infections in adults: Background, specific aims, and methods

Background The Need To Improve Antibiotic Prescription for Acute Respiratory Infections 1. The epidemic increase in antibiotic-resistant Streptococcus pneumoniae is an ambulatory care problem. Excessive use of antibiotics in ambulatory practice has contributed to the emergence and spread of antibiotic-resistant bacteria in the community (1-4). Penicillin resistance in S. pneumoniae has increased in an epidemic manner in the past 10 years (5, 6). Resistance to macrolides, doxycycline, trimethoprimsulfamethoxazole, and second- and third-generation cephalosporins has also increased. Special attention to antibiotic-resistance profiles of S. pneumoniae is warranted, since this pathogen is the leading cause of community-acquired bacterial pneumonia, bacterial meningitis, bacterial sinusitis, and otitis media in the United States (7). 2. Previous antibiotic use is an important risk factor for carriage of and infection with antibiotic-resistant Streptococcus pneumoniae. The major risk factors for carriage of and infection with antibiotic-resistant S. pneumoniae are geographic location, recent exposure to antibiotics, and exposure to young children. Carriage of S. pneumoniae (and antibiotic-resistant S. pneumoniae) primarily occurs in the nasopharynx and oropharynx of susceptible hosts (8, 9). Factors contributing to the spread of S. pneumoniae (such as close contact and viral respiratory infections) are also associated with the spread of antibiotic-resistant S. pneumoniae (10-12). For example, carriage and transmission of antibiotic-resistant S. pneumoniae are greatest during winter months and in environments that facilitate the transmission of respiratory secretions (8). The prevalence of carriage of S. pneumoniae and antibiotic-resistant S. pneumoniae appears to be greatest in young children; up to one third of children who visit health clinics are reported to be nasopharyngeal carriers of antibiotic-resistant S. pneumoniae (13-15). The prevalence of S. pneumoniae colonization in the upper airways in adults is about 5%; this value increases if children are present in the household (10). Although the risks for transmission of antibiotic-resistant S. pneumoniae mirror those for S. pneumoniae, numerous retrospective and prospective carriage studies have also identified previous antibiotic use, especially for a prolonged period (for example, as prophylaxis against recurrent acute otitis media), to be the most significant risk factor for carriage and subsequent spread of antibiotic-resistant S. pneumoniae (14-18). The risk for carriage of antibiotic-resistant S. pneumoniae is two to nine times greater in persons who have recently used antibiotics. A precipitously rapid increase in antibiotic resistance has also been observed for strains of S. pneumoniae in blood, cerebrospinal fluid, and joint fluid in the United States since 1986, when invasive antibiotic-resistant S. pneumoniae isolates were rare or absent (5). Like carriage of antibiotic-resistant S. pneumoniae, invasive infection with antibiotic-resistant S. pneumoniae is associated with previous antibiotic use (6, 19-22). When invasive infection with antibiotic-resistant S. pneumoniae occurs, antibiotics with poor central nervous system penetration and bacteriostatic (instead of bactericidal) properties must sometimes be used. Treatment failures have been reported in patients with pneumococcal meningitis after therapy with penicillin, chloramphenicol, clarithromycin, ceftriaxone, and cefotaxime (12, 23-26). The management of outpatient bacterial infections, such as acute otitis media, becomes substantially more difficult because of high rates of antibiotic-resistant S. pneumoniae in children with such infections (27, 28). However, few studies have quantified the clinical impact of antibiotic-resistant S. pneumoniae on morbidity, mortality, and health care costs in children or adults. In a study of hospitalized patients with severe pneumococcal pneumonia in Spain, where a high prevalence of antibiotic-resistant S. pneumoniae preceded the current increase in the United States, no association was seen between antibiotic resistance and mortality (29). However, most patients had intermediate-level penicillin resistance; in such patients, serum and lung interstitium concentrations of antibiotic are sufficiently high to overcome resistance. A recent study of U.S. adults hospitalized with community-acquired pneumonia due to S. pneumoniae found that mortality was significantly associated with high-level antibiotic-resistant S. pneumoniae (minimum inhibitory concentration 4 g/mL), after exclusion of deaths that occurred within the first 2 to 4 days of hospitalization (30). Exclusion of early deaths is justified, since antibiotic therapy has not been shown to affect early mortality in adults with antibiotic-susceptible pneumococcal disease (31). Because of the current increase in antibiotic resistance in community bacterial pathogens, many experts are predicting an impending postantibiotic era (2-4). 3. Most antibiotic prescriptions in the ambulatory setting are for acute respiratory infections. Intervention strategies aimed at reducing community use of antibiotics must address the management of acute respiratory infections. These illnesses are the most frequent reasons for seeking medical attention in the United States, and they are associated with up to 75% of total antibiotic prescriptions each year (32). Transmission of S. pneumoniae is enhanced during viral acute respiratory infection through increased respiratory and nasal secretions (10). As a result, antibiotic treatment of viral acute respiratory infections is particularly problematic, since it may selectively promote the acquisition and spread of antibiotic-resistant bacteria by patients. Specific acute respiratory infections that must be targeted for reducing unnecessary antibiotic use in adults are uncomplicated acute bronchitis (not including acute exacerbations of chronic bronchitis), acute sinusitis, pharyngitis, and nonspecific upper respiratory tract infection (including the common cold). These diagnoses are usually made in the presence of a clinical syndrome with a predominant clinical feature, so that prominent acute cough is taken to mean acute bronchitis, prominent nasal and sinus symptoms are thought to signify sinusitis, and prominent acute sore throat is considered pharyngitis. Acute respiratory symptoms in the absence of a predominant symptom are typically diagnosed as upper respiratory tract infection. Each of these syndromes can be caused by a multitude of different viruses and, on occasion, bacteria. The degree of excess prescription of antibiotics varies for each diagnosis. Antibiotic treatment of a cold, an upper respiratory tract infection, or acute bronchitis is almost always inappropriate because the vast majority of these syndromes have a nonbacterial cause. Antibiotic treatment of sinusitis and pharyngitis is sometimes justified but should be limited to appropriate subsets of patients. Potential Benefit and Harm of Adherence to Principles of Appropriate Antibiotic Prescription Potential Benefits of Indiscriminant Antibiotic Prescription Some clinicians may prescribe antibiotics because they believe that a very small fraction of patients might benefit or they hope to prevent the remote case of a bad outcome (and a potential lawsuit). A theoretical clinical benefit of treating viral respiratory tract infections with antibiotics cannot be excluded. A truism for all clinical trials performed in medicine is that a benefit of treatment cannot be excluded for outcomes that occur less frequently than the sample size can detect (that is, there will always be specific outcomes that were not or cannot be measured). For example, invasive bacterial disease, such as sepsis or bacterial meningitis, is too rare an event to be evaluated in a randomized, controlled trial with enough power to exclude a potential benefit of antibiotic treatment. The incidence of bacterial meningitis in the United States is about 3 per 100 000 persons in the general population (1995) (33) or about 9 per 100 000 persons with an office visit for an acute respiratory illness (unpublished data based on the National Ambulatory Medical Care Survey, 1997). Indiscriminant use of antibiotics may also in theory prevent complications of other undiagnosed bacterial infections, such as acute rheumatic fever. While these hypothetical benefits are possible, no evidence supports their existence. Potential Harms of Indiscriminant Antibiotic Prescription In contrast to the theoretical clinical benefit of indiscriminant prescription of antibiotics, the potential harm of this practice is well established at the level of the patient and society. At the patient level, risks include allergic reactions (such as urticaria, rash, and anaphylaxis), adverse reactions (such as gastrointestinal discomfort or yeast infections), and drugdrug interactions (such as QT interval prolongation caused by warfarin and oral contraceptives), as well as the increased likelihood that a pneumococcal infection in the ensuing months will be due to an antibiotic-resistant strain. At the societal level, the adverse effects of indiscriminant antibiotic use on rates of antibiotic resistance are well established, and the effects on health care costs (for antibiotics and office visits) are straightforward. Finally, indiscriminant antibiotic use could serve to inappropriately medicalize viral illnesses. This tendency not only usurps the ability of individual persons to care for self-limited illnesses but also carries large associated costs in terms of unnecessary office visits and prescriptions. Potential Benefits of Limiting Indiscriminant Antibiotic Prescription Besides decreasing the risk for the harms noted above, the intended result of efforts to decrease indiscriminant antibiotic use in the ambulatory setting is to reduce (and preferably reverse) the increase in antibiotic-re

Principles of Appropriate Antibiotic Use for Acute Pharyngitis in Adults

In this guideline, we present the evidence and make specific recommendations on how clinicians can distinguish and diagnose pharyngitis caused by group A -hemolytic streptococcus (GABHS). We also discuss when antibiotic use is beneficial and which antibiotics should be used. This guideline will not cover gonococcal pharyngitis and diphtheria, for which the appropriateness of immediate antibiotic treatment is well established. The numbers in square brackets are cross-references to the numbered sections in the accompanying background paper, Principles of Appropriate Antibiotic Use for Acute Pharyngitis in Adults: Background, which is part 2 of this guideline (see pages 509-517). Acute Pharyngitis Acute pharyngitis accounts for 1% to 2% of all visits to outpatient departments, physician offices and emergency departments. A wide range of infectious agents produces acute pharyngitis, but viruses are the most common cause. Approximately 5% to 15% of adult cases are caused by GABHS. In some patients, it can be important to identify an infectious cause other than GABHS (for example, gonococcal pharyngitis, EpsteinBarr virus, and acute HIV infection), but in the vast majority of cases, acute pharyngitis in an otherwise healthy adult is self-limited and rarely produces significant sequelae [1.1]. Antimicrobial agents are prescribed to a substantial majority of patients with acute pharyngitis because of perceived patient expectations or physician desires to avoid such potential complications as rheumatic fever and acute glomerulonephritis. Consequently, this discussion will focus on the diagnosis and treatment of acute GABHS pharyngitis in adult patients. These guidelines do not apply to patients with a history of rheumatic fever, valvular heart disease, immunosuppression, or recurrent or chronic pharyngitis (symptoms > 7 days) or to patients whose sore throats are not due to acute pharyngitis. They are also not intended to apply during a known epidemic of acute rheumatic fever or streptococcal pharyngitis, or in nonindustrialized countries in which the endemic rate of acute rheumatic fever is much higher than in the United States [1.2]. Although it has been more than 50 years since treatment of streptococcal pharyngitis with penicillin was shown to prevent acute rheumatic fever, diagnosing GABHS infection remains a subject of controversy. This is in part because the best criterion standard for the diagnosis has not been definitively established, and testing for a significant increase in antistreptolysin titers and use of throat swab cultures cannot provide real-time resultsthat is, results that are available when a decision regarding antibiotic use must be made. Because only patients with GABHS (and a few other rare bacterial agents) benefit from antimicrobial therapy, the goal of the diagnostic evaluation should be to predict which patients have a high likelihood of GABHS pharyngitis. Diagnosis Although recovery of GABHS from throat cultures is reported in many clinical trials and may be the best available predictor of treatment response, it has poor testretest agreement; does not always correlate with antistreptolysin titers; and produces results that vary depending on technique, the site in which the sample is obtained and plated, the culture medium, the conditions in which the culture is incubated, and whether results are checked at 24 or 48 hours. Throat cultures also fail to distinguish acute infection from the carrier state. Furthermore, because culture results are not available at the time of the index visit, and a delayed decision about use of antibiotics eliminates the primary benefit of antimicrobial therapy in adults (symptom relief), we do not include use of throat culture for clinical decision making in this set of management principles. In addition, there are several reasonable approaches to the diagnosis of GABHS in an otherwise healthy adult, such as use of clinical criteria alone or use of rapid antigen testing as an adjunct to clinical screening. Either of these strategies is associated with reasonable diagnostic accuracy (approximate sensitivity 70%, specificity 70%) and allows treatment decisions to be made early in the course of illness, when patients can receive symptomatic benefit [4.04.2]. Although use of clinical screening (history and physical examination) alone would leave some patients with GABHS untreated and would result in overtreatment of others, it would prompt treatment of most patients with GABHS while dramatically decreasing excess antibiotic use. The most reliable predictors include tonsillar exudates, tender anterior cervical lymphadenopathy, absence of cough, and history of fever. Several studies examining these four criteria in a clinical decision rule indicate that in patients who have three or four of the criteria, the sensitivity and specificity (compared with those of throat culture) are approximately 75% and 75%, respectively [4.2.1]. Rapid antigen tests for GABHS, when compared with the criterion standard of throat culture, have widely variable reported sensitivity (58% to 96%) and specificity (63% to 100%), depending on the type of test and practice setting of the trial. These rapid antigen tests can be done at the bedside, and treatment decisions can be made in real time. The potential advantage of the rapid antigen tests compared with clinical models is that they have approximately the same sensitivity and perhaps greater specificity for predicting results of throat culture. The disadvantage is that many patients would need to be tested to achieve the possible gain in specificity beyond that provided by clinical information alone. This would shift economic costs from a few extra prescriptions to many extra rapid antigen tests. Performing rapid antigen testing only in individual patients with an intermediate clinical probability of GABHS (those with three, or perhaps two, of the four clinical variables) and withholding antimicrobial agents from those with negative results would decrease antimicrobial use, compared with a clinical decision alone, at the cost of potentially undertreating an additional small group of patients with GABHS. Unfortunately, although many physicians currently perform rapid antigen tests, there is evidence that they frequently prescribe antimicrobial agents even when test results are negative [4.2.2]. Treatment Reasons to consider prescribing antimicrobials to treat streptococcal pharyngitis include a desire to prevent rheumatic fever, prevent acute glomerulonephritis, prevent suppurative complications, decrease contagion, and ameliorate symptoms. Although reported rates may underestimate the true incidence of acute rheumatic fever, repeatedly low and unchanging reported rates over more than a decade prompted the Centers for Disease Control and Prevention to drop acute rheumatic fever from active national surveillance in 1994. It is still important to consider local epidemics and to be prepared to revise the approach to treatment if evidence of an outbreak exists, although the number of discrete outbreaks of acute rheumatic fever in the United States is very small and should not overly influence physician behavior. Similarly, poststreptococcal acute glomerulonephritis does occur but is extremely rare, even in the absence of antibiotic treatment. Furthermore, there is no evidence that antimicrobial therapy decreases incidence of this complication [3.0, 3.1]. The incidence of suppurative complications, regardless of treatment with antimicrobials, is also small. The most common complication today is peritonsillar abscess (quinsy). Recent clinical trials provide some evidence that targeting antimicrobials to a subset of patients with higher clinical likelihood of GABHS may prevent quinsy. In another recent review of GABHS pharyngitis in practice, however, the authors reported that the risk for peritonsillar abscess was not reduced because many affected patients do not present for care until after the complication has developed [3.2, 3.3]. Streptococcal infection often occurs in epidemics, and contagion is a problem in areas of overcrowding or close contacts. Antimicrobial agents lead to far greater microbiological eradication of streptococcus by 48 to 72 hours. However, the presymptomatic incubation period for GABHS is 2 to 5 days, during which the infection can be unknowingly transmitted to others. The effect of treatment on spread of disease in a noninstitutionalized adult population is unknown. Nevertheless, it is not unreasonable to consider whether an adult is living in close quarters with small children when making clinical decisions about treatment [3.4]. The relief of patient suffering is an appropriate concern of physicians as well as patients. Antimicrobial agents, when instituted within 2 to 3 days of symptom onset, hasten symptomatic improvement among patients in whom throat culture ultimately grows GABHS or in populations in which a high likelihood of GABHS pharyngitis is identified clinically, but not in those with a negative culture. Symptoms seem to resolve 1 to 2 days sooner when antipyretics and other comfort measures are also instituted. One recent trial among unselected patients with acute pharyngitis found that symptom duration was strongly related to patient satisfaction, and patient satisfaction was closely related to whether the physician addressed the patients concerns rather than to use of antibiotics. This further supports limiting antimicrobials to the subset of patients most likely to benefit and reemphasizes the importance of the quality of the physicianpatient interaction [3.5]. If antimicrobial treatment is to be instituted, physicians should choose an agent with the narrowest possible spectrum of action that still covers GABHS. Thus, penicillin is the first choice for patients without a penicillin allergy, and erythromycin is the first choice for penicillin-allergic patients. To date, there is no evidence of GABHS res

Requirements and Definitions in Conflict of Interest Policies of Medical Journals

CONTEXT Conflicts of interest (COIs) may influence medical literature. However, it is unclear whether medical journals have consistent policies for defining and soliciting COI disclosures. OBJECTIVE To determine the prevalence of author COI policies, requirements for signed disclosure statements, and variability in COI definitions among medical journals. DESIGN A cross-sectional survey of Instructions for Authors and manuscript submission documents, including authorship responsibility forms, for high-impact medical journals across 35 subject categories available from March through October 2008. MAIN OUTCOME MEASURE Presence of language referring to COI disclosure in the Instructions for Authors or manuscript submission documents. RESULTS Of 256 journals, 89% had author COI policies. Fifty-four percent required authors to sign a disclosure statement, and 77% provided definitions of COI. Most definitions were limited to direct financial relationships; a minority of journals requested disclosure of other potential conflicts such as personal relationships (42%), paid expert testimony (42%), relationships with other organizations (26%), or travel grants (12%). The prevalence of policies varied by subject category: all internal medicine, respiratory medicine, and toxicology journals studied had comprehensive COI definitions, with 19 of these 24 journals requiring signed disclosure attestations. In contrast, 6 of 19 geriatrics, radiology, and rehabilitation journals requested author COI disclosure. Most journals that officially endorsed International Committee of Medical Journal Editors guidelines had COI policies (68/69), compared with 84% of journals not endorsing the guidelines (158/187). CONCLUSIONS In 2008, most medical journals with relatively high impact factors had author COI policies available for public review. Among journals, there was substantial variation in policies for solicitation of author COIs and in definitions of COI.

Performance of a Decision Rule to Predict Need for Computed Tomography Among Children With Blunt Head Trauma

OBJECTIVE. To assess the ability of the NEXUS II head trauma decision instrument to identify patients with clinically important intracranial injury (ICI) from among children with blunt head trauma. METHODS. An analysis was conducted of the pediatric cohort involved in the derivation set of National Emergency X-Radiography Utilization Study II (NEXUS II), a prospective, observational, multicenter study of all patients who had blunt head trauma and underwent cranial computed tomography (CT) imaging at 1 of 21 emergency departments. We determined the test performance characteristics of the 8-variable NEXUS II decision instrument, derived from the entire NEXUS II cohort, in the pediatric cohort (0–18 years of age), as well as in the very young children (<3 years). Clinically important ICI was defined as ICI that required neurosurgical intervention (craniotomy, intracranial pressure monitoring, or mechanical ventilation) or was likely to be associated with significant long-term neurologic impairment. RESULTS. NEXUS II enrolled 1666 children, 138 (8.3%) of whom had clinically important ICI. The decision instrument correctly identified 136 of the 138 cases and classified 230 as low risk. A total of 309 children were younger than 3 years, among whom 25 had ICI. The decision instrument identified all 25 cases of clinically important ICI in this subgroup. CONCLUSIONS. The decision instrument derived in the large NEXUS II cohort performed with similarly high sensitivity among the subgroup of children who were included in this study. Clinically important ICI were rare in children who did not exhibit at least 1 of the NEXUS II risk criteria.

Conflict of Interest Disclosure Policies and Practices in Peer‐reviewed Biomedical Journals

OBJECTIVE: We undertook this investigation to characterize conflict of interest (COI) policies of biomedical journals with respect to authors, peer-reviewers, and editors, and to ascertain what information about COI disclosures is publicly available. METHODS: We performed a cross-sectional survey of a convenience sample of 135 editors of peer-reviewed biomedical journals that publish original research. We chose an international selection of general and specialty medical journals that publish in English. Selection was based on journal impact factor, and the recommendations of experts in the field. We developed and pilot tested a 3-part web-based survey. The survey included questions about the presence of specific policies for authors, peer-reviewers, and editors, specific restrictions on authors, peer-reviewers, and editors based on COI, and the public availability of these disclosures. Editors were contacted a minimum of 3 times. RESULTS: The response rate for the survey was 91 (67%) of 135, and 85 (93%) of 91 journals reported having an author COI policy. Ten (11%) journals reported that they restrict author submissions based on COI (e.g., drug company authors’ papers on their products are not accepted). While 77% report collecting COI information on all author submissions, only 57% publish all author disclosures. A minority of journals report having a specific policy on peer-reviewer 46% (42/91) or editor COI 40% (36/91); among these, 25% and 31% of journals state that they require recusal of peer-reviewers and editors if they report a COI. Only 3% of respondents publish COI disclosures of peer-reviewers, and 12% publish editor COI disclosures, while 11% and 24%, respectively, reported that this information is available upon request. CONCLUSION: Many more journals have a policy regarding COI for authors than they do for peer-reviewers or editors. Even author COI policies are variable, depending on the type of manuscript submitted. The COI information that is collected by journals is often not published; the extent to which such “secret disclosure” may impact the integrity of the journal or the published work is not known.

Principles of appropriate antibiotic use for acute pharyngitis in adults : Background

The following principles of appropriate antibiotic use for adults with acute pharyngitis apply to immunocompetent adults without complicated comorbid conditions, such as chronic lung or heart disease, and history of rheumatic fever. They do not apply during known outbreaks of group A streptococcus.1. Group A beta-hemolytic streptococcus (GABHS) is the causal agent in approximately 10% of adult cases of pharyngitis. The large majority of adults with acute pharyngitis have a self-limited illness, for which supportive care only is needed.2. Antibiotic treatment of adult pharyngitis benefits only those patients with GABHS infection. All patients with pharyngitis should be offered appropriate doses of analgesics and antipyretics, as well as other supportive care.3. Limit antibiotic prescriptions to patients who are most likely to have GABHS infection. Clinically screen all adult patients with pharyngitis for the presence of the four Centor criteria: history of fever, tonsillar exudates, no cough, and tender anterior cervical lymphadenopathy (lymphadenitis). Do not test or treat patients with none or only one of these criteria, since these patients are unlikely to have GABHS infection. For patients with two or more criteria the following strategies are appropriate: a) Test patients with two, three, or four criteria by using a rapid antigen test, and limit antibiotic therapy to patients with positive test results; b) test patients with two or three criteria by using a rapid antigen test, and limit antibiotic therapy to patients with positive test results or patients with four criteria; or c) do not use any diagnostic tests, and limit antibiotic therapy to patients with three or four criteria. 4. Throat cultures are not recommended for the routine primary evaluation of adults with pharyngitis or for confirmation of negative results on rapid antigen tests when the test sensitivity exceeds 80%. Throat cultures may be indicated as part of investigations of outbreaks of GABHS disease, for monitoring the development and spread of antibiotic resistance, or when such pathogens as gonococcus are being considered.5. The preferred antibiotic for treatment of acute GABHS pharyngitis is penicillin, or erythromycin in a penicillin-allergic patient.

The Quantity and Quality of Scientific Graphs in Pharmaceutical Advertisements

We characterized the quantity and quality of graphs in all pharmaceutical advertisements in the 1999 issues of 10 U.S. medical journals. Four hundred eighty-four unique advertisements (of 3,185 total advertisements) contained 836 glossy and 455 small-print pages. Forty-nine percent of glossy page area was nonscientific figures/images, 0.4% tables, and 1.6% scientific graphs (74 graphs in 64 advertisements). All 74 graphs were univariate displays, 4% were distributions, and 4% contained confidence intervals for summary measures. Extraneous decoration (66%) and redundancy (46%) were common. Fifty-eight percent of graphs presented an outcome relevant to the drug’s indication. Numeric distortion, specifically prohibited by FDA regulations, occurred in 36% of graphs.

The availability of references and the sponsorship of original research cited in pharmaceutical advertisements

Background: The primary goal of pharmaceutical advertisements is to convince physicians to prescribe the manufacturers product. We sought to determine what materials are cited in support of claims in pharmaceutical ads and medical research articles, and whether health care professionals seeking to verify the claims could obtain these references. Methods: We reviewed 438 unique ads from the 1999 issues of 10 American medical journals, and a random sample of 400 references in medical research articles selected from the same journals. We classified references as journal article, data on file, meeting abstract or presentation, book or monograph, marketing report, prescribing information, government document or Internet site. We attempted to confirm or obtain each reference through library and Internet searches or by direct request from the manufacturer. The main outcome we sought to determine was the availability of the reference to a clinician. We also ascertained the source of funding for original research cited in the ads and the research articles. Results: In the 438 ads with medical claims, 126 contained no references and 312 contained 721 unique references. Of these ad references, 55% (396/721) cited journal articles and 19% (135/721) cited data on file. In contrast, in the sample of research article references, 88% (351/400) cited journal articles and 8% (33/400) cited books. Overall, 84% of the citations from the ads were available: 98% of journal articles, 86% of books, 71% of meeting abstracts or presentations and 20% of data-on-file references. In all, 99% of the sample of research article references were available. We determined that 58% of the original research cited in the pharmaceutical ads was sponsored by or had an author affiliated with the products manufacturer, as compared with 8% of the articles cited in the research articles. Interpretation: Many pharmaceutical ads contain no references for medical claims. Although references to journal articles were usually obtainable, other published sources were not as easily acquired. The majority of unpublished data-on-file references were not available, and the majority of original research cited to substantiate claims in the pharmaceutical ads was funded by or had authors affiliated with the products manufacturer.

NHAMCS: Does It Hold Up to Scrutiny?

In this month’s Annals, we have an unprecedented look at the National Hospital Ambulatory Medical Care Survey (NHAMCS) from inside the National Center for Health Statistics. McCaig and Burt explain what NHAMCS can and cannot tell us and provide a glimpse of the survey’s future. NHAMCS is the largest extant national emergency department (ED) database, the data source for more than 90 articles in Annals alone. The popularity of NHAMCS with researchers is likely due to the rigor of the sampling methods—which permit reconstitution of a population that resembles the entire US population—and its availability online at no cost. Unfortunately, a series of recent articles suggests that despite these appealing features, problems with data quality in NHAMCS render some conclusions based on these data questionable at best. In this editorial, I examine these problems and explain how well-meaning investigators may reach erroneous conclusions and unintentionally mislead readers. Additionally, I will propose steps that investigators should take when preparing to use the NHAMCS database in articles submitted to Annals (Table). All databases used for research, including the large national probability samples such as NHAMCS, must satisfy 2 basic tenets; they must not be prone to sampling bias and the data must be accurate. Although NHAMCS receives high marks on the former, several articles raise doubts about the latter. An argument is only as strong as its weakest link, and the high marks NHAMCS scores for its sampling methods mean little if its data-gathering process receives a D grade for reliably and accuracy.