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      Quinolone Safety and Efficacy

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          To the Editor: Richard Frothingham should be commended for providing added perspective on the matter of quinolone selection. His letter to the editor emphasizing the paramount importance of a well-established safety profile and documented clinical efficacy in severe infections before a "wholesale change" to the newer quinolones is an appropriate response to Michael Scheld's essay on maintaining quinolone class efficacy in which a "correct spectrum" strategy of using the most potent quinolone to treat the presumed or confirmed pathogen was described and advocated (1). In his article, Frothingham reminds us that serious adverse drug effects in patients led to the withdrawal or restriction of 4 quinolones in the last decade and that safety may differ substantially among the quinolones discussed in Scheld's review (ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin) (2). With the exception of labeling changes regarding glucose homeostasis abnormalities associated with gatifloxacin therapy, the subject of quinolone safety is centered on torsades de pointes. Data published in 2001 are cited; these consist of a review of crude rates of US cases of torsades de pointes from January 1996 through May 2, 2001 (3). However, these data only capture adverse drug reports for the first full year gatifloxacin and moxifloxacin were widely available in the United States. The last several years have seen dramatic uptake of all 3 respiratory quinolones. Use of these agents is pervasive in both community and hospital settings. Indeed, the Infectious Diseases Society of America, American Thoracic Society, and Sinus and Allergy Health Partnership have since published revised consensus statements calling for the use of these agents earlier in therapy for community-acquired pneumonia and bacterial sinusitis (4–6). December 2004 marked 5 years since the Food and Drug Administration approved gatifloxacin and moxifloxacin and 8 years since the approval of levofloxacin. As a result of tens of millions of patient exposures, we now have more robust data to work with and are better able to make informed and meaningful safety comparisons, particularly with respect to torsades de pointes, a rare, life-threatening cardiac arrhythmia infrequently associated with quinolone therapy. With respect to efficacy, Frothingham writes that ciprofloxacin and levofloxacin have been studied in patient populations with more severe illness, and trials of the newer quinolones have enrolled patients with predominantly mild or moderate community-acquired infections and low overall death rates in comparison. However, a cursory review of the literature suggests otherwise. As with gatifloxacin and moxifloxacin, few peer-reviewed, published data support the use of levofloxacin in the treatment of severe, life-threatening infections at the currently approved doses of 500 mg or 750 mg. Indeed, the 2 references cited raise serious concern about the suitability of levofloxacin at currently recommended doses for severe and life-threatening infections. In File et al. (7) levofloxacin was studied in only 16 patients classified as having severe community-acquired pneumonia; in Norrby et al. (8) a dose of levofloxacin 500 mg every 12 hours was studied in severe community-acquired pneumonia. At this time, other published studies support the use of levofloxacin at a dose of 500 mg every 12 hours in severe and life-threatening infections: an approved regimen in Europe but not yet approved in the United States (9,10). In summary, differences in quinolone safety are evidenced by labeling changes to gatifloxacin, the only quinolone to carry a specific warning regarding glucose homeostasis abnormalities. However, the incidence of torsades de pointes associated with each of these agents is ripe for further investigation as we pass the 5-year mark of approval for the new respiratory quinolones. An update of those data on the rate of torsades cited by Frothingham and published in 2001 would provide meaningful guidance to clinicians. Currently, with the exception of ciprofloxacin, each of these quinolones contains labeling guidance in the form of a warning (gatifloxacin, moxifloxacin) or a precaution (levofloxacin), and concurrent use with class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmics should be avoided to reduce the risk of torsades de pointes per current product labeling. Ciprofloxacin remains the only quinolone to date based on multiple, head-to-head, well-controlled, published trials to have established efficacy and safety in a severely ill patient population at approved doses. A paucity of published clinical data exist on the use of gatifloxacin, levofloxacin and moxifloxacin in hospitalized patients with severe, life-threatening infections. Therefore, the respective manufacturers must establish safety and efficacy in well-controlled studies with the resultant data made available in peer-reviewed journals before these agents are fully embraced for these infections.

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          Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention.

           ,  T File,  Derek Fine (2001)
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            Update of Practice Guidelines for the Management of Community-Acquired Pneumonia in Immunocompetent Adults

            Introduction The Infectious Diseases Society of America (IDSA) produced guidelines for community-acquired pneumonia (CAP) in immunocompetent adults in 1998 and again in 2000 [1, 2]. Because of evolving resistance to antimicrobials and other advances, it was felt that an update should be provided every few years so that important developments could be highlighted and pressing questions answered. We addressed those issues that the committee believed were important to the practicing physician, including suggestions for initial empiric therapy for CAP. In some cases, only a few paragraphs were needed, whereas, in others, a somewhat more in-depth discussion was provided. Because many physicians focus on the tables rather than on the text of guidelines, it was decided that all of the information dealing with the initial empiric treatment regimens should be in tabular format with footnotes (tables 1–3). The topics selected for updating have been organized according to the headings used in the August 2000 CAP guidelines published in Clinical Infectious Diseases [2]. The major headings were “Epidemiology,” “Diagnostic Evaluation,” “Special Considerations,” “Management,” “Prevention,” and “Performance Indicators,” and each section had a number of subentries. Our current topics are either updates of specific subheadings or are new contributions, and the committee's recommendations are given at the beginning of each section. A summary of prior IDSA recommendations presented in 2000 and the updated and new recommendations can be found in table 4. Ratings of the strength of the supporting evidence and the quality of the data are given in parentheses after each recommendation, and the grading system used to categorize them is in table 5. Table 1 Initial empiric therapy for suspected bacterial community-acquired pneumonia (CAP) in immunocompetent adults. Table 3 Susceptibility of Streptococcus pneumoniae isolates to commonly used antimicrobial agents, stratified by susceptibility to penicillin, according to 2001 data from the Center for Disease Control's Active Bacterial Core Surveillance (n = 3418) and 2002 NCCLS susceptibility definitions. Table 4 Recommendations for management of community-acquired pneumonia (CAP) in immunocompetent adults: summary of prior Infectious Diseases Society of America (IDSA) recommendations of 2000 and updated and new recommendations for 2003 (in bold). Table 5 Infectious Diseases Society of America—United States Public Health Service grading system for rating recommendations in clinical guidelines. The next guidelines for the treatment of CAP will be a joint effort by the IDSA and the American Thoracic Society (ATS). A working group representing both societies has been formed and is already at work on the next CAP treatment guidelines. Update on The Initial Site of Treatment Decision Recommendation 1 . The initial site of treatment should be based on a 3-step process: (1) assessment of preexisting conditions that compromise safety of home care; (2) calculation of the pneumonia PORT (Pneumonia Outcomes Research Team) Severity Index (PSI) with recommendation for home care for risk classes I, II, and III; and (3) clinical judgment (A-II). Recommendation 2 . For discharge criteria, during the 24 h prior to discharge to the home, the patient should have no more than 1 of the following characteristics (unless this represents the baseline status): temperature, >37.8°C; pulse, >100 beats/min; respiratory rate, >24 breaths/min; systolic blood pressure, 3200 patients with CAP, implementation of the PSI with high- and moderate-intensity implementation strategies resulted in a statistically significantly greater proportion of low-risk patients being treated in the outpatient setting. The committee continues to support use of the PSI as a means of risk stratification and urges that this process be combined with careful assessment of the patient and use of clinical judgment. Although discharge criteria are not part of the initial site of treatment decision, there are data showing that appropriate use of recommended criteria can reduce mortality [8]. The recommended discharge criteria are that, during the 24 h before discharge to the home, the patient should have no more than 1 of the following characteristics (unless this represents the baseline status): temperature, >37.8°C; pulse, >100 beats/min; respiratory rate, >24 breaths/min; systolic blood pressure, 8000 probable cases have been reported from >28 countries worldwide [27]. The heaviest concentrations of cases were identified in mainland China, Hong Kong, and Taiwan, with Singapore, Hanoi, and Toronto also experiencing severe outbreaks. Transmission and infection control. A majority of early cases occurred among health care workers and family members reporting direct contact with patients who had SARS, and children were relatively spared. Subsequently, rapid international spread by infected airline passengers brought the disease to most continents. Most transmission has been from ill patients to their close contacts, with a relatively high degree of communicability. Direct contact with respiratory secretions and spread via respiratory droplets have been presumed to be the most important modes of transmission, and barrier nursing precautions (with hand washing) have been advocated as the mainstay of control measures. However, the transmission to 13 persons staying in a Hong Kong hotel, to airline passengers, to >200 residents of a single apartment block, and to a number of other persons without recognized close contact with a known case has raised the likelihood of more-remote transmission, whether by fomite or by airborne routes [28, 29]. Health care workers encountering a possible case of SARS should take meticulous safety precautions and should seek immediate advice from an expert in SARS infection control [30]. Protective measures should include standard precautions (hand washing and eye protection), contact precautions (use of gown and gloves), and airborne precautions (isolating the patient in a negative-pressure room and use of well-sealed N95 or greater respirators for all who enter the room). Additional precautions are advised for aerosol-generating procedures, which include many procedures routinely performed on patients undergoing ventilatory support, because of the evidence for transmission to health care workers in these settings, despite the routine use of airborne precautions [31]. This additional protection may include higher levels of respirators (N100 filters or powered air-purifying respirators), full-body isolation suits, and an outer disposable layer of equipment that can be discarded to reduce possible fomite spread [32]. Infection-control precautions should be continued for at least the duration of symptoms, and some precautions may be warranted for a longer period because of the possibility of more-prolonged viral shedding. Updated information should be sought from active reliable Web sites, such as those of the CDC ( and the World Health Organization (WHO; Pathogen. Although a number of potential pathogens were initially identified in patients with SARS, including C. pneumoniae, influenza virus B, and human metapneumovirus, it is now clear that a novel coronavirus is the etiologic agent. Several different laboratories identified an identical strain of this novel coronavirus in patients with SARS by culture of respiratory secretions and lung tissue specimens, electron microscopy, RT-PCR, and seroconversion [33, 34]. Inoculation of macaques with the novel coronavirus, but not with human metapneumovirus, produced a severe respiratory illness akin to SARS in humans [35]. The findings of preliminary reports of detection of the SARS coronavirus in civet cats and a number of other species are provocative, and a number of investigators are attempting to confirm the findings. The sequence of the viral genome has been completed, placing the agent in the coronavirus family and either as a distant member of 1 of the 3 previously described antigenic groups or in a fourth antigenic group [36]. Diagnosis. For surveillance purposes, using clinical and epidemiologic criteria, SARS has been categorized as suspect or probable cases, and the working definitions proposed by WHO have been modified for applicability to particular countries. To meet the CDC criteria for a suspected case, a patient must have fever (temperature, >38°C) and ⩾1 clinical finding of moderate respiratory illness (e.g., cough, shortness of breath, and hypoxia), as well as epidemiologic criteria (travel within 10 days before onset of symptoms to an area with community transmission of SARS, or close contact within 10 days before onset of symptoms with a person known or suspected of having SARS infection) [37, 38]. A probable case is one that meets the definition for suspected cases and, in addition, has either radiographic evidence of pneumonia, respiratory distress syndrome, or autopsy findings consistent with pneumonia or respiratory distress syndrome without an identifiable cause. Current versions of these definitions have changed as new information has become available; in particular, the updated definition of “areas with community transmission of SARS” should be obtained from the CDC or WHO Web sites [37, 39]. As of July 2003, the CDC case definition [37, 38] also incorporates laboratory criteria, although most cases reported in the United States and internationally have been defined using clinical and epidemiologic criteria alone [39]. Culture of the SARS coronavirus is considered solid evidence of infection. However, the various generations of RT-PCR assays have had problems, both with false-positive results and with inconsistent detection of viral genome in both the first days of illness and in the convalescent phase [40]. Because antibodies to SARS coronavirus have not been found in the general population, background SARS coronavirus antibodies do not appear to be a substantial concern [33, 34]. However, the current serologic assays (both ELISA and IFA formats) do not reliably detect antibodies until the titers increase substantially after the second week of illness [40]. According to the CDC, suspect or probable cases are considered to be laboratory confirmed if SARS coronavirus is isolated, if antibody to SARS coronavirus is detected, or if 2 different RT-PCR assays performed with different specimen aliquots identify the coronavirus RNA. Because of the possibility of false-negative results of cultures and RT-PCR assays, only the absence of antibody in a serum specimen obtained >28 days after symptom onset is considered by the CDC to be a negative laboratory test result for SARS coronavirus [37, 38]. These diagnostic tests are not yet available for routine use in clinical laboratories. Clinicians should conduct thorough diagnostic testing to rule out other etiologies in patients suspected of having SARS. Respiratory specimens and blood, serum, and stool samples should be saved for additional testing until a specific diagnosis has been made, and convalescent-phase serum samples should be obtained from patients whose cases meet the SARS case definition and forwarded to state and local health departments for testing at the CDC. Clinical features. There is a characteristic clinical picture associated with the SARS in several well-described studies, although distinguishing SARS from other causes of pneumonia remains a challenge [39, 41, 42]. After an incubation period of ∼2–10 days (median, 4 days), the most characteristic initial symptom is fever, with or without cough or dyspnea. Chills, myalgia, and progressive respiratory distress often accompany the persisting fever during the first week of illness, and mild gastrointestinal symptoms are present in some patients. The typical fever and the observation that pharyngitis, rhinorrhea, sneezing and conjuctivitis are unusual may help to distinguish patients with SARS from persons with more-common viral upper respiratory tract infections. On initial presentation, there are typically few physical findings, with a normal chest examination or mild crackles without wheezing, and no rash. The chest radiograph may appear normal or show only mild abnormalities during the first few days, but progression to a bilateral lower lobe interstitial infiltrate is most characteristic. Other radiographic findings are also described, including lobar pneumonia, shifting atelectasis, and multiple focal areas of consolidation, particularly in the periphery of the lungs [43]. Routine laboratory findings include normal-to-low leukocyte counts, with absolute lymphopenia in approximately one-half the patients. Platelet counts are also normal to low. Mild to moderately elevated transaminase, lactate dehydrogenase, and creatinine phosphokinase levels are seen in 30%–70% of cases. In most probable SARS cases, symptoms resolve spontaneously after the first week. In ⩾20% of patients, symptoms progress over 2–3 weeks to the more-severe respiratory distress syndrome, and the patients require intensive care and ventilatory support. Approximately 10%–15% of cases have died of progressive respiratory failure. Mortality is strongly age-dependent, with mortality of >50% for patients older than 65 years. Patients with underlying chronic heart or lung disease also appear to be at elevated risk for severe disease, although previously healthy younger adults have also died. The most prominent pathological findings in lung tissue samples on autopsy have been diffuse alveolar damage with hyaline membrane formation, interstitial mononuclear infiltration, and desquamation of pneumocytes; in some cases, tissues have shown intra-alveolar hemorrhage, necrotic debris within small airways, organizing pneumonia, or the presence of multinucleated giant cells without viral inclusions [33]. Therapy. A variety of treatments have been attempted, but there are no data from controlled studies, and the available anecdotal evidence is not persuasive that any of the treatment approaches thus far have demonstrated efficacy. Most patients have been treated throughout the illness with supplemental oxygen, intravenous fluids, and other supportive measures; broad-spectrum antibacterial agents have also been given, but these would not be expected to have any effect on the coronavirus infection itself. Early in vitro testing of ribavirin and other antiviral compounds against the novel coronavirus has not produced persuasive evidence of in vitro activity [44, 45]. Corticosteroids and a number of antiviral compounds, including the neuraminidase inhibitors and ribavirin, have been used empirically, but, in the future, use of antiviral compounds for SARS should be done within the context of a controlled clinical trial, because of the importance of identifying efficacious treatments and the lack of evidence of efficacy for any treatment to date. SARS progressed rapidly from a localized outbreak in southern China to an epidemic with global reach. As of this writing, the epidemic has waned in most of the heavily affected areas, in association with vigorous public health interventions, including community mobilization and quarantine measures on a scale not seen during the past half-century or more. A second wave of infections in Toronto and isolated clusters of new cases elsewhere highlight the dangers of complacency as the acute phase of the epidemic passes. The impact of the epidemic on regional economies, international travel, and medical care is only beginning to be recognized, and the future of SARS is uncertain. It seems possible that SARS will be an important cause of pneumonia in the future, and the screening of outpatients at risk for SARS may become part of the pneumonia evaluation. Infectious diseases physicians will need to ensure that they maintain awareness and that triage procedures adequately provide for the standard, contact, and airborne precautions necessary to protect their fellow workers from infection. Special Considerations: Treatment of Bacteremic Pneumococcal Pneumonia—New Addition Recommendation 1 . Initial empiric therapy prior to availability of culture data for a patient ill enough to require admission to a hospital ward can be with a β-lactam plus macrolide combination or a respiratory fluoroquinolone alone (A-I). If sufficiently ill to need intensive care unit (ICU) management and if Pseudomonas infection is not a concern, a combination of a β-lactam plus either a macrolide or a respiratory fluoroquinolone should be used (B-III). Recommendation 2 . Once culture data are available and it is known that the patient has pneumococcal pneumonia with bacteremia without evidence to support infection with a copathogen, treatment will depend upon in vitro susceptibility results. If the isolate is penicillin susceptible, a β-lactam (penicillin G or amoxicillin) alone may be used (B-II). If the isolate is penicillin resistant, cefotaxime, ceftriaxone, or a respiratory fluoroquinolone or other agent indicated by in vitro testing may be used (A-III). Comment . The mortality rate for bacteremic pneumococcal pneumonia is 6%–20%, yet it was always assumed that monotherapy in such cases was sufficient. The guidelines from the IDSA, the ATS, and the Canadian Infectious Diseases Society and Canadian Thoracic Society recommend a macrolide and β-lactam regimen or a fluoroquinolone alone for empiric treatment of patients admitted to a hospital ward and a macrolide or fluoroquinolone plus a β-lactam for patients admitted to the ICU for whom Pseudomonas aeruginosa infection has been excluded. In the former instance, therapy was based on the results of studies that showed that such a regimen was associated with a shorter length of stay and reduced mortality [46, 47]. For ICU patients, this recommendation was based on a lack of efficacy data about fluoroquinolones as monotherapy for severe CAP, as well as concerns about infection with a resistant pathogen. Three retrospective studies have suggested that dual therapy that included a macrolide given empirically reduced mortality associated with bacteremic pneumococcal pneumonia [48–50]. However, the fact that they were neither prospective nor randomized studies meant that they had significant design limitations. It is important to note that these studies evaluated the effects of initial empiric therapy before the results of blood cultures were known. They did not examine effects of pathogen-specific therapy after the results of blood cultures were available, and the panel believes that the results of these studies do not contradict the principles of pathogen-directed therapy. Two possible explanations for the improved results with a macrolide are the concurrent presence of atypical pathogens (Mycoplasma pneumoniae, C. pneumoniae, or Legionella species) and the immunomodulating effects of macrolides [51]. A prospective, randomized trial is ultimately needed to determine the best regimen without bias or confounding variables distorting the answer. A retrospective analysis of Medicare data involving >700 patients aged ⩾65 years with severe pneumococcal pneumonia by the Fine criteria showed that monotherapy with a third-generation cephalosporin was as effective as any other regimen involving a single drug or combination therapy. The end points were in-hospital mortality and 30-day mortality (P. Houck, personal communication). Empiric therapy for patients with CAP admitted to a hospital ward can be with either a β-lactam plus macrolide regimen or a respiratory fluoroquinolone alone. For those ill enough to require admission to the ICU and in whom Pseudomonas infection is not an issue, initial empiric treatment started before any culture data are available should be with a β-lactam plus either a macrolide or a fluoroquinolone. However, if blood cultures subsequently reveal a pathogen such as S. pneumoniae and there is no evidence of infection with a copathogen, the decision to continue with combination therapy or to switch to a single agent is probably best determined on an individual basis [52]. Variables to consider include the patient's age and any comorbid conditions, as well as the clinical, bacteriological, and radiographic response to therapy. If a single agent is to be used, the committee believes that bacteremic pneumococcal pneumonia should be treated with penicillin G or ampicillin if the pathogen is penicillin susceptible, and it should be treated with cefotaxime, ceftriaxone, a respiratory fluoroquinolone, or other agent indicated by in vitro testing, if the pathogen is penicillin resistant. Special Considerations: Update on Legionnaires' Disease Recommendation 1 . Preferred diagnostic tests are the urinary antigen assay and culture of respiratory secretions on selective media (A-II). Recommendation 2 . Testing for Legionella species is appropriate for any patient hospitalized with enigmatic pneumonia (C-II). This test is recommended in patients with enigmatic pneumonia sufficiently severe to require care in the ICU, in the presence of an epidemic, or if there is failure to respond to a β-lactam (A-III). Recommendation 3 . Treatment for legionnaires' disease is appropriate when there is epidemiologic evidence of this disease, despite negative diagnostic test results (B-III). Recommendation 4 . The preferred treatment for legionnaires' disease for hospitalized patients is azithromycin or a fluoroquinolone (moxifloxacin, gatifloxacin, and levofloxacin; gemifloxacin is only available as an oral formulation) (B-II). For patients who do not require hospitalization, acceptable antibiotics include erythromycin, doxycycline, azithromycin, clarithromycin, or a fluoroquinolone (A-II). Treatment should be initiated as rapidly as is feasible (A-II). Comment . Legionella is implicated in 0.5%–6% of CAP cases in most hospital-based series [53–57]. Risk is related to exposure, increasing age, smoking, and compromised cell-mediated immunity, such as occurs in transplant recipients [58]. Epidemiologic risk factors include recent travel with an overnight stay outside of the home, exposure to spas, recent changes in domestic plumbing, renal or hepatic failure, diabetes, and systemic malignancy [58–60]. Mortality rates are 5%–25% among immunocompetent hosts [57, 59, 61]. Legionella was 1 of 2 major respiratory tract pathogens in patients with CAP who required admission to the ICU, according to 7 of 9 recent reviews [62]. Some authorities feel that the following constellation of clinical features suggests this diagnosis: high fever, hyponatremia, CNS manifestations, lactate dehydrogenase levels of >700 U/mL, or severe disease [57]. However, several studies have demonstrated difficulty in distinguishing individual cases of legionnaires' disease from other causes of CAP on the basis of initial clinical findings, nonspecific laboratory findings, or radiograph findings [63–65]. A clinical scoring system that uses a combination of clinical and nonspecific laboratory findings is neither sufficiently specific nor sensitive to enable accurate diagnosis, although a high score may help direct cost-effective specific laboratory testing [57]. Methods of laboratory detection include culture, serologic tests, direct fluorescent antibody (DFA) staining, urinary antigen assay, and PCR [66]. DFA stains require substantial expertise for interpretation, and selection of reagents is critical. PCR is expensive, and there are no FDA-cleared reagents. The 2 recommended tests are the urinary antigen assay and culture of respiratory secretions. The urinary antigen assay for Legionella pneumophila serogroup 1 is not technically demanding and reliably and rapidly detects up to 80%–95% of community-acquired cases of legionnaires' disease, but it is substantially less sensitive for nosocomial cases because of frequent involvement of serogroups other than serogroup 1 [60]. Culture on selective media detects all but very rare strains but is technically demanding and requires 3–7 days [58, 67]. Testing for Legionella species is appropriate for any patient hospitalized with enigmatic pneumonia; testing is recommended for patients with enigmatic pneumonia sufficiently severe to require hospitalization in an ICU, pneumonia in a compromised host, in the presence of an epidemic, and failure to respond to treatment with a β-lactam. It should also be emphasized that no laboratory test for legionnaires' disease detects all patients with the disease. In the appropriate clinical and epidemiologic settings, therapy for legionnaires' disease should be given or continued even if the results of Legionella-specific tests are negative [58, 67]. The preferred therapy for legionnaires' disease depends upon the severity of illness, the underlying health of the patient, and patient drug tolerance. Otherwise healthy patients with mild pneumonia not requiring hospitalization may be treated with a wide variety of antimicrobial agents, including erythromycin, tetracycline, doxycycline, azithromycin, clarithromycin, levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin [57, 68, 69]. Azithromycin or a fluoroquinolone (moxifloxacin, gatifloxacin, or levofloxacin) are recommended for severe disease (gemifloxacin is only available in an oral formulation). A delay in therapy is associated with an increased mortality rate, and treatment should be started as soon as possible [70]. The duration of treatment should be 10–21 days, but it should be less for azithromycin because of its long half-life [57, 68]. Special Considerations: Viral Causes Of Cap—New Addition Recommendation 1 . Respiratory syncytial virus (RSV) antigen detection tests are readily available but are insensitive for detecting infections in adults and are not generally recommended for adults (C-III). Recommendation 2 . A rapid antigen detection assay for influenza virus is recommended for rapid detection of this pathogen for epidemiologic purposes and/or treatment (C-II). Tests that distinguish between influenza A and B are generally preferred (C-III). Recommendation 3 . Early treatment (within 48 h after onset of symptoms) is effective in the treatment of influenza A using amantadine, rimantadine, oseltamivir, or zanamivir and is effective in the treatment influenza B using oseltamivir and zanamivir (B-I). Use of these drugs is not recommended for uncomplicated influenza with a duration of symptoms of >48 h (D-I), but these drugs may be used to reduce viral shedding in hospitalized patients or for influenza pneumonia (C-III). Recommendation 4 . Empiric treatment of suspected bacterial superinfection of influenza should provide activity against S. pneumoniae, Staphylococcus aureus, and Haemophilus influenzae with antibiotics such as amoxicillin-clavulanate, cefpodoxime, cefprozil, cefuroxime, or a respiratory fluoroquinolone (B-III). Recommendation 5 . Pneumonia caused by varicella zoster virus (VZV) or herpes simplex virus (HSV) should be treated with parenteral acyclovir (A-II). Recommendation 6 . There is no antiviral agent with established efficacy for the treatment of adults with pulmonary infections involving parainfluenza virus, RSV, adenovirus, metapneumovirus, the SARS agent, or Hantavirus (D-I). Comment . Respiratory tract viruses are common causes of often serious cases of pneumonia, particularly in elderly patients, patients with chronic obstructive lung disease, and patients with comorbidities. One prospective study of 1029 chronically ill adults found respiratory viral infections in 35%–48% (depending on age) of those hospitalized for an acute respiratory condition (i.e., pneumonia, tracheobronchitis, exacerbations of asthma, or chronic obstructive lung disease) and that influenza, RSV, or parainfluenza virus accounted for 75% of these viral infections [71]. A review of influenza and RSV for the 1976–1977 through 1998–1999 seasons suggested that influenza was responsible for an average of 36,155 respiratory- and circulatory-associated deaths per year in the United States. Particularly vulnerable were persons with cardiopulmonary disease and persons aged >65 years, especially the “elderly elderly,” defined as persons >85 years of age [72]. RSV was implicated in an average of 11,321 cardiopulmonary deaths per year, with most deaths occurring among elderly persons and persons with chronic cardiac or pulmonary diseases. Other viral causes of respiratory tract infections are parainfluenza virus and, less commonly, adenovirus, metapneumovirus, HSV, VZV, and measles. (SARS is discussed in a separate section in this guideline.) Metapneumovirus is a recently described paramyxovirus, which appears to be a potentially important viral respiratory tract pathogen, causing pneumonia in both children and adults [73, 74]. The clinical presentations of viral pneumonias and the spectrum of associated agents are highly dependent on patient age, comorbidities, and immune status. Approximately 10% of immunocompetent adults hospitalized with CAP have evidence of viral infection, but this varies from 4%–39% in different studies [75]. A recent report from the United Kingdom showed serologic evidence of a viral infection in 23% of 267 patients hospitalized with CAP, with influenza and RSV in 20% and 4%, respectively, of the total [76]. Influenza and other viruses can cause primary viral pneumonias; secondary bacterial infections are common in hospitalized adults, and the reported frequency has ranged widely, from 26% to 77% in different studies [75]. The most common cause of bacterial superinfection is S. pneumoniae, but S. aureus has been found in up to one-quarter of patients in earlier studies. In the absence of a characteristic exanthem, no clinical or radiographic criteria are able to reliably distinguish persons with viral infection from persons with bacterial infection. Cultures for respiratory viruses (except for shell vial methods, which can yield a diagnosis the next day) and serologic studies are usually too slow to be useful in individual patient treatment. Rapid antigen detection aimed at influenza can provide a diagnosis in 15–30 min, but test performance varies with the specific test used, sample type, duration of illness, and patient age. Sensitivity is ∼50%–70% in adults [77, 78], so that negative test results do not exclude the diagnosis; these tests have not generally proven to be superior to physician diagnosis based on the presence of fever and typical symptoms in the presence of an epidemic [79], but some rapid tests can distinguish between influenza A and B strains, which may have therapeutic implications. Antigen tests for RSV detection are insensitive ( 50 years, others at risk for influenza complications, and household contacts of high-risk persons should receive inactivated influenza vaccine, as recommended by the Advisory Committee on Immunization Practices (ACIP) (A-I). The injected inactivated vaccine is the preferred formulation for most persons at risk of complications associated with influenza, for household contacts of high-risk persons, and for health care workers (A-1). The intranasally administered live, attenuated vaccine (FluMist; Aventis) is an alternative vaccine formulation for some persons aged 5–49 years without chronic underlying diseases, including immunodeficiency, asthma, and chronic medical conditions (C-I). Influenza vaccine should be offered to persons at hospital discharge or during outpatient treatment during the fall and winter (C-III). Health care workers in inpatient and outpatient settings and long-term care facilities should receive annual influenza immunization (A-I). Recommendation 2 . Pneumococcal polysaccharide vaccine (Pneumovax; MedImmune [marketed by Wyeth in the United States]) is recommended for use, according to current ACIP guidelines, including use for persons aged >65 years and for those with selected high-risk concurrent diseases (B-II). Vaccination may be done either at hospital discharge or during outpatient treatment (C-III). Comment . Vaccination against influenza and pneumococcus infection is the mainstay of prevention against pneumonia for older adults. A systematic review that included 1 randomized trial and 20 cohort studies showed that, for frail older adults, influenza vaccine had an efficacy (1-OR) of 53% for preventing pneumonia, 50% for preventing hospitalization, and 68% for preventing death [116]. A recent large observational study of adults >65 years found that vaccination against influenza was associated with a reduction in the risk of hospitalization for cardiac disease (19% reduction), cerebrovascular disease (16%–23% reduction), and pneumonia or influenza (29–32% reduction), as well as a reduction in the risk of death due to all causes (48%–50% reduction) [117]. In long-term care facilities, vaccination of health care workers with influenza vaccine is an important preventive health measure. Data from 2 cluster randomized trials have shown benefit [118, 119]. Potter et al. [118] randomized 12 long-term facilities to either the offer of vaccination of health care workers or to no offer of vaccination. Vaccination of health care workers was associated with a reduction in total patient mortality rate, from 17% to 10%. Carman et al. [119] conducted a randomized trial involving 20 geriatric care hospitals in which they compared influenza vaccination of health care workers with no vaccination. Vaccination of health care workers significantly reduced mortality among elderly people who had a stay of >6 months in hospitals where health care workers were vaccinated, compared with hospitals where they were not (OR, 0.58; 95% CI, 0.04–0.84; P = .014). Influenza vaccine effectiveness varies among influenza seasons, with effectiveness being higher when the vaccine antigens are more closely matched to the circulating strains. Pneumococcal polysaccharide vaccine has not been consistently effective in randomized, double-blind, controlled trials involving elderly individuals. Results of one randomized clinical trial suggested that the polysaccharide vaccine provided some protection against pneumococcal pneumonia among high-risk elderly persons [120]; 2 other trials did not demonstrate efficacy against pneumonia or bronchitis without bacteremia [121, 122], although the use of nonspecific diagnostic methods may have limited the studies' ability to find an effect [123]. Two open-label trials have suggested protection against pneumococcal pneumonia among elderly residents of long-term care facilities [124, 125]. Postlicensure epidemiological studies, including a recent large observational study, involving elderly persons and younger adults with certain chronic medical conditions have documented effectiveness of pneumococcal polysaccharide vaccines for prevention of invasive infection (bacteremia and meningitis) but not for prevention of pneumonia without bacteremia [126–130]. The overall effectiveness against invasive pneumococcal disease among immunocompetent persons aged ⩾65 years is 75% [126], although efficacy may decrease with advancing age [128]. Older adults may be benefiting from vaccination of children against pneumococcal disease because of decreased pneumococcal transmission. In 2000, a protein-polysaccharide conjugate vaccine targeting 7 pneumococcal serotypes (Prevnar; Wyeth Lederle Vaccines) was licensed for use in young children in the United States. According to data from the CDC's Active Bacterial Core Surveillance (ABCS), rates of invasive pneumococcal disease (e.g., primary bacteremia, pneumonia with bacteremia, and meningitis) among children aged 6 months of age who are at increased risk for complications from influenza [133]. Target groups for vaccination include persons aged ⩾50 years; persons of any age who reside in a nursing home or other long-term care facility, who have a chronic disorder of the pulmonary or cardiovascular systems, including asthma, or who have a chronic illness that required regular outpatient follow-up or hospitalization in the prior year, such as chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications or by HIV); and women who will be in the second or third trimester of pregnancy during the influenza season. All health care workers or others whose work involves any patient contact, including contact with nursing home residents, should receive influenza vaccine annually to prevent possible transmission to patients. In addition, vaccination of all children 6–23 months and their caregivers is encouraged. An intranasally administered, live, attenuated, influenza virus vaccine was approved in 2003 by the FDA. ACIP guidelines on use were published in September 2003 [134]. The live, attenuated vaccine is approved for use and is currently recommended as an option for vaccination of healthy persons aged 5–49 years. Advantages of the new vaccine include the potential to induce both mucosal and systemic immune responses and the acceptability of administration using the intranasal rather than intramuscular route. Because it is made from live, attenuated virus, however, care should be taken to avoid administering it to certain persons. Inactivated influenza vaccine (the injected formulation) rather than the intranasally administered, live, attenuated virus vaccine should be given to persons aged 65 years of age and for younger adults with certain chronic diseases (such as diabetes, cardiovascular disease, lung disease, alcohol abuse, liver disease, CSF leaks, or renal failure) or immune system disorders (such as sickle cell disease, nephrotic syndrome, HIV infection, hematologic malignancies, or long-term use of immunosuppressive medications) [135]. A second dose is recommended after 5 years for persons with immune system disorders and for persons aged >65 years whose first dose was received before the age of 65 years. The efficacy of revaccination is unknown. A recent model suggested that it may be cost-effective to vaccinate all adults aged ⩾50 years, especially African American persons and those with comorbid conditions [136]. The ACIP is considering changes to the vaccine recommendations that would include vaccinating all adults aged ⩾50 years and listing smokers among those with chronic illnesses who should be vaccinated at an earlier age. Update on Macrolides Recommendation 1 . A macrolide is recommended as monotherapy for selected outpatients, such as those who were previously healthy and not recently treated with antibiotics (A-I). Recommendation 2 . A macrolide plus a β-lactam is recommended for initial empiric treatment of outpatients in whom resistance is an issue and for hospitalized patients (A-I). Comment . The macrolides constitute one of the most popular and long-standing classes of antibiotics in clinical use. The class includes 3 drugs in North America: erythromycin, azithromycin, and clarithromycin and has played a significant role in the management of CAP because of its activity against S. pneumoniae and the atypical pathogens. Although erythromycin is the least expensive of these 3 drugs, it is not used as often because of gastrointestinal intolerance and lack of activity against H. influenzae. In the United States, pneumococci were uniformly susceptible to macrolides until the late 1980s [137]. As the result of a steady increase in the rate of resistance, at present, in the United States, ∼25% of all pneumococci show some level of resistance to macrolides [138–140], ranging from 17% in the Northeast to 35% in the Southeast [138]. There are 2 principal mechanisms of resistance: (1) an alteration of the macrolide binding site by methylation in the 23S rRNA, encoded by erm(B), and (2) an efflux pump, encoded by mef(A), by which bacteria expel macrolides [141, 142]. The methylase causes high level resistance (MIC of erythromycin, 128 mg/mL), whereas the efflux pump produces lower-level resistance (MIC of erythromycin, 1–64 mg/mL) that some experts believe can be overcome by increasing antibiotic concentrations. Rarer mechanisms of (high-level) resistance include alterations of ribosomal proteins L4 or L22 that are adjacent to domain V [143, 144]. In the United States, one-third of macrolide-resistant strains carry erm(B), and the other two-thirds carry mef(A) [138, 140]. The level of resistance among mef(A) strains has steadily increased in the past few years [139, 145]. In other words, even those organisms that historically had lower-level resistance have become increasingly resistant to achievable levels of macrolides [139, 146]. In Europe, a higher proportion of pneumococci are macrolide resistant, and erm(B) is responsible in the majority of isolates [147]. Rates of resistance are lower in Canada than in the United States, and they are higher in the Far East than in Europe [148]. Despite the reports of increasing resistance in vitro, the number of clinical failures has not kept pace. Reports of clinical failures in pneumococcal pneumonia by Dixon [149], Fogarty et al. [150], Kelley et al. [151], and Lonks et al. [152] have failed to provide convincing numbers to match the laboratory phenomena. Why is this? There are a number of possible answers. First of all, mortality may be a relatively insensitive measure of the impact of resistance. Also, to detect treatment failures, one would have to use monotherapy with a drug to which the etiologic agent is known to be resistant. In support of the IDSA approach is the relatively small number of reported failures and the fact that, when patients such as those described by Kelley et al. [151] and Lonks et al. [152] were hospitalized and treated with a β-lactam and a macrolide, they all survived. What then is the role for macrolides in 2003? For outpatients, we believe that, for those who have previously been healthy and who have not been treated with antibiotics for any reason within the preceding 3 months, a macrolide alone is adequate (table 1). An advanced macrolide, such as azithromycin or clarithromycin, may be used alone for patients with comorbidities, such as chronic obstructive pulmonary disease, diabetes, renal or congestive heart failure, or malignancy, who have not been previously treated with antibiotics. For selected outpatients and inpatients, it is clear that, given together with a β-lactam, the macrolides still play an important role. If the infection is caused by macrolide-resistant S. pneumoniae, it is highly likely that the β-lactam will still be effective, and, if caused by one of the atypical pathogens, the macrolide will certainly have a role to play. The Ketolides—New Addition Recommendation . Telithromycin may have a role as an alternative to macrolides for treatment of patients with CAP. At this time, however, it is not yet FDA approved. Comment . The ketolides, which are semisynthetic derivatives of 14-membered macrolides, were developed specifically to be effective against macrolide-resistant, gram-positive cocci. Structural modifications at the positions of 3, 6, and 11–12 have altered and improved the pharmacokinetic and antimicrobial activity of the parent compounds, and pharmaceutical manufacturers are seeking approval for their use in CAP, acute exacerbation of chronic bronchitis, and acute sinusitis. The antibacterial activity of macrolides and ketolides is dependent on inhibition of bacterial protein synthesis. The main differences between them, however, are that, although macrolides bind to only 1 contact site within the 23S ribosomal subunit (domain V), ketolides bind more avidly to domain V and, in addition, bind to a second site on the 23S subunit (domain II). Telithromycin also has some affinity for the efflux pump [153–155]. These differences explain why ketolides remain active against pathogens with both erm- and mef-mediated resistance. In vitro, telithromycin is active against S. pneumoniae, including macrolide-resistant strains, as well as H. influenzae and Moraxella catarrhalis [156, 157]. The drug also inhibits Legionella, Mycoplasma, and Chlamydophilia species [158, 159]. The drug is given once daily at a dose of 800 mg and appears to be well tolerated while achieving ratios of tissue to plasma of ⩾500 and 16.8 in alveolar macrophages and epithelial lining fluid, respectively [160, 161]. Data from 3 randomized, controlled, double-blind CAP trials comparing telithromycin with amoxicillin, clarithromycin, and trovafloxacin suggest that the ketolide is as effective as the comparators [162–164]. Data available to date suggest that the ketolides may have an important role to play in the treatment of CAP caused by macrolide-resistant S. pneumoniae, but more studies involving sicker patients are required before its full value can be appreciated. The drug has not yet been approved by the FDA. S. Pneumoniae With Reduced Susceptibility to Fluoroquinolones in North America—New Addition Recommendation 1 . Fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin) are recommended for initial empiric therapy of selected outpatients with CAP (A-I). Other options (macrolides and doxycycline) are generally preferred for uncomplicated infections in outpatients (A-I). Recommendation 2 . Fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin) may be used as monotherapy for patients with CAP who are admitted to a hospital ward (A-I). With the exception of gemifloxacin (no intravenous formulation), they may be used as part of a combination for patients with CAP admitted to an ICU (C-III). Comment . Since publication of the 2000 guidelines, fluoroquinolone agents have been more widely used to treat pneumonia, yet, at the same time, several compounds have been withdrawn because of serious safety concerns, and resistance to this class of drugs has been increasing. Emergence of S. pneumoniae with reduced susceptibility to the fluoroquinolones has been described in Canada, Spain, Hong Kong, eastern and central Europe, and, to a lesser extent, the United States [147, 165–171]. In some countries, resistance has been due to multiple serotypes, whereas, in others, it has resulted predominantly from a single serotype, such as the 23F clone in Hong Kong [165, 167]. Fluoroquinolone resistance in S. pneumoniae is primarily due to mutations in the genes encoding the target topoisomerase enzymes, namely parC, which encodes the A subunit of DNA topoisomerase IV, and/or gyrA, which encodes the A subunit of DNA gyrase. Resistance occurs in a stepwise fashion, with first-step mutations in one target gene (either parC or gyrA) resulting in low-level resistance and second-step mutations in the other target genes (either parC or gyrA) leading to higher levels of resistance. In Canada, Chen et al. [165] found that the prevalence of ciprofloxacin-resistant pneumococci (MIC, ⩾4 ∼g/mL) increased from 0% in 1993 to 1.7% in 1997–1998 (P = .01). In adults, the prevalence increased from 0% in 1993 to 3.7% in 1998. In addition to the increase in the prevalence of pneumococci with reduced susceptibility to fluoroquinolones, the degree of resistance also increased. From 1994 to 1998, there was a statistically significant increase in the proportion of isolates with an MIC of ciprofloxacin of ⩾32 ∼g/mL (P = .04). In 2002, the Canadian Bacterial Surveillance Network reported that the prevalence of levofloxacin-resistant pneumococci (MIC, 8 ∼g/mL) was 4% in sputum isolates recovered from patients >65 years of age [172]. Rates of resistance in the United States are 13,000 patients with pneumonia who were hospitalized in 1998 and 1999 and who had not received antibiotics before admission. Initial therapy within 4 h after arrival at the hospital was associated with reduced mortality in the hospital (severity-adjusted OR, 0.85; 95% CI, 0.76–0.95). Mean length of stay was 0.4 days shorter among patients who received antimicrobials within 4 h than among those whose initial therapy was given later. Improved outcomes were associated with timely therapy independent of PSI class and the presence of congestive heart failure. These findings are consistent with those of several previous studies [182, 184–187]. The committee supports the early initiation of antibiotic therapy in patients requiring hospitalization for CAP. Smoking has a well-established association with morbidity and mortality, especially in the form of chronic lung disease and cancer. It is also associated with a substantial risk of pneumococcal bacteremia; one report showed that smoking was the strongest of multiple risks for invasive pneumococcal disease in immunocompetent, nonelderly adults [188]. Smoking is also identified as a risk for Legionella infection [58]. Smoking cessation should be attempted when smokers are hospitalized; this is particularly important and relevant when these patients are hospitalized for pneumonia. Conflict of Interest Disclosure Lionel A. Mandell has received research funding from Bayer, Bristol-Myers Squibb, and Pharmacia; has been a consultant for Bayer, Pfizer, Aventis, Ortho-McNeil, and Janssen-Ortho; and has been on the speakers' bureau for Pfizer, Aventis, Wyeth, Ortho-McNeil, and Bayer. Thomas M. File, Jr., has received research funding from Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Cubist, GlaxoSmithKline, Pfizer, and Wyeth; has been a consultant for Aventis, Bayer, Cubist, GlaxoSmithKline, Ortho-McNeil, Pfizer, and Wyeth; and has been on the speakers' bureau for Abbott, Aventis, Bayer, GlaxoSmithKline, Merck, Ortho-McNeil, Pfizer, and Wyeth.
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              Executive summary ☆

              Treatment guidelines developed by the Sinus and Allergy Health Partnership for acute bacterial rhinosinusitis (ABRS) were originally published in 2000. These guidelines were designed to: (1) educate clinicians and patients (or patients’ families) about the differences between viral and bacterial rhinosinusitis; (2) reduce the use of antibiotics for nonbacterial nasal/sinus disease; (3) provide recommendations for the diagnosis and optimal treatment of ABRS; (4) promote the use of appropriate antibiotic therapy when bacterial infection is likely; and (5) describe the current understanding of pharmacokinetic and pharmacodynamics and how they relate to the effectiveness of antimicrobial therapy. The original guidelines are updated here to include the most recent information on management principles, antimicrobial susceptibility patterns, and therapeutic options. Burden of disease An estimated 20 million cases of ABRS occur annually in the United States. According to National Ambulatory Medical Care Survey (NAMCS) data, sinusitis is the fifth most common diagnosis for which an antibiotic is prescribed. Sinusitis accounted for 9% and 21% of all pediatric and adult antibiotic prescriptions, respectively, written in 2002. The primary diagnosis of sinusitis results in expenditures of approximately $3.5 billion per year in the United States. Definition and diagnosis of ABRS ABRS is most often preceded by a viral upper respiratory tract infection (URI). Allergy, trauma, dental infection, or other factors that lead to inflammation of the nose and paranasal sinuses may also predispose individuals to developing ABRS. Patients with a “common cold” (viral URI) usually report some combination of the following symptoms: sneezing, rhinorrhea, nasal congestion, hyposmia/anosmia, facial pressure, postnasal drip, sore throat, cough, ear fullness, fever, and myalgia. A change in the color or the characteristic of the nasal discharge is not a specific sign of a bacterial infection. Bacterial superinfection may occur at any time during the course of a viral URI. The risk that bacterial superinfection has occurred is greater if the illness is still present after 10 days. Because there may be cases that fall out of the “norm” of this typical progression, practicing clinicians need to rely on their clinical judgment when using these guidelines. In general, however, a diagnosis of ABRS may be made in adults or children with symptoms of a viral URI that have not improved after 10 days or worsen after 5 to 7 days. There may be some or all of the following signs and symptoms: nasal drainage, nasal congestion, facial pressure/pain (especially when unilateral and focused in the region of a particular sinus), postnasal drainage, hyposmia/anosmia, fever, cough, fatigue, maxillary dental pain, and ear pressure/fullness. Physical examination provides limited information in the diagnosis of ABRS. While sometimes helpful, plain film radiographs, computed tomography (CT), and magnetic resonance imaging scans are not necessary for cases of ABRS. Microbiology of ABRS The most common bacterial species isolated from the maxillary sinuses of patients with ABRS are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, the latter being more common in children. Other streptococcal species, anaerobic bacteria and Staphylococcus aureus cause a small percentage of cases. Bacterial resistance in ABRS The increasing prevalence of penicillin nonsusceptibility and resistance to other drug classes among S pneumoniae has been a problem in the United States, with 15% being penicillin-intermediate and 25% being penicillin-resistant in recent studies. Resistance to macrolides and trimethoprim/sulfamethoxazole (TMP/SMX) is also common in S pneumoniae. The prevalence of β-lactamase-producing isolates of H influenzae is approximately 30%, while essentially all M catarrhalis isolates produce β-lactamases. Resistance of H influenzae to TMP/SMX is also common. Antimicrobial treatment guidelines for ABRS These guidelines apply to both adults and children. When selecting antibiotic therapy for ABRS, the clinician should consider the severity of the disease, the rate of progression of the disease, and recent antibiotic exposure. The guidelines now divide patients with ABRS into two general categories: (1) those with mild symptoms who have not received antibiotics within the past 4 to 6 weeks, and (2) those with mild disease who have received antibiotics within the past 4 to 6 weeks or those with moderate disease regardless of recent antibiotic exposure. The difference in severity of disease does not imply infection with a resistant pathogen. Rather, this terminology indicates the relative degree of acceptance of possible treatment failure and the likelihood of spontaneous resolution of symptoms—patients with more severe symptoms are less likely to resolve their disease spontaneously. The primary goal of antibiotic therapy is to eradicate bacteria from the site of infection, which, in turn, helps (1) return the sinuses back to health; (2) decrease the duration of symptoms to allow patients to resume daily activities more quickly; (3) prevent severe complications such as meningitis and brain abscess; and (4) decrease the development of chronic disease. Severe or life-threatening infections with or without complications are rare, and are not addressed in these guidelines. Prior antibiotic use is a major risk factor associated with the development of infection with antimicrobial-resistant strains. Because recent antimicrobial exposure increases the risk of carriage of and infection due to resistant organisms, antimicrobial therapy should be based upon the patient’s history of recent antibiotic use. The panel’s guidelines, therefore, stratify patients according to antibiotic exposure in the previous 4 to 6 weeks. Lack of response to therapy at ≥72 hours is an arbitrary time established to define treatment failures. Clinicians should monitor the response to antibiotic therapy, which may include instructing the patient to call the office or clinic if symptoms persist or worsen over the next few days. The predicted bacteriologic and clinical efficacy of antibiotics in adults and children has been determined according to mathematical modeling of ABRS developed by Michael Poole, MD, PhD, based on pathogen distribution, resolution rates without treatment, and in vitro microbiologic activity. Antibiotics can be placed into the following relative rank order of predicted clinical efficacy for adults: 90% to 92% = respiratory fluoroquinolones (gatifloxacin, levofloxacin, moxifloxacin), ceftriaxone, high-dose amoxicillin/clavulanate (4 g/250 mg/day), and amoxicillin/clavulanate (1.75 g/250 mg/day); 83% to 88% = high-dose amoxicillin (4 g/day), amoxicillin (1.5 g/day), cefpodoxime proxetil, cefixime (based on H influenzae and M catarrhalis coverage), cefuroxime axetil, cefdinir, and TMP/SMX; 77% to 81% = doxycycline, clindamycin (based on gram-positive coverage only), azithromycin, clarithromycin and erythromycin, and telithromycin; 65% to 66% = cefaclor and loracarbef. The predicted spontaneous resolution rate in patients with a clinical diagnosis of ABRS is 62%. Antibiotics can be placed into the following relative rank order of predicted clinical efficacy in children with ABRS: 91% to 92% = ceftriaxone, high-dose amoxicillin/clavulanate (90 mg/6.4 mg per kg per day) and amoxicillin/clavulanate (45 mg/6.4 mg per kg per day); 82% to 87% = high-dose amoxicillin (90 mg/kg per day), amoxicillin (45 mg/kg per day), cefpodoxime proxetil, cefixime (based on H influenzae and M catarrhalis coverage only), cefuroxime axetil, cefdinir, and TMP/SMX; and 78% to 80% = clindamycin (based on gram-positive coverage only), cefprozil, azithromycin, clarithromycin, and erythromycin; 67% to 68% = cefaclor and loracarbef. The predicted spontaneous resolution rate in untreated children with a presumed diagnosis of ABRS is 63%. Recommendations for initial therapy for adult patients with mild disease (who have not received antibiotics in the previous 4 to 6 weeks) include the following choices: amoxicillin/clavulanate (1.75 to 4 g/250 mg per day), amoxicillin (1.5 to 4 g/day), cefpodoxime proxetil, cefuroxime axetil, or cefdinir. While TMP/SMX, doxycycline, azithromycin, clarithromycin, erythromycin, or telithromycin may be considered for patients with β-lactam allergies, bacteriologic failure rates of 20% to 25% are possible. Failure to respond to antimicrobial therapy after 72 hours should prompt either a switch to alternate antimicrobial therapy or reevaluation of the patient (see Table 4).When a change in antibiotic therapy is made, the clinician should consider the limitations in coverage of the initial agent. Recommendations for initial therapy for adults with mild disease who have received antibiotics in the previous 4 to 6 weeks or adults with moderate disease include the following choices: respiratory fluoroquinolone (eg, gatifloxacin, levofloxacin, moxifloxacin) or high-dose amoxicillin/clavulanate (4 g/250 mg per day). The widespread use of respiratory fluoroquinolones for patients with milder disease may promote resistance of a wide spectrum of organisms to this class of agents. Ceftriaxone (parenteral, 1 to 2 g/day for 5 days) or combination therapy with adequate gram-positive and negative coverage may also be considered. Examples of appropriate regimens of combination therapy include high-dose amoxicillin or clindamycin plus cefixime, or high-dose amoxicillin or clindamycin plus rifampin. While the clinical effectiveness of ceftriaxone and these combinations for ABRS is unproven; the panel considers these reasonable therapeutic options based on the spectrum of activity of these agents and on data extrapolated from acute otitis media studies. Rifampin should not be used as monotherapy, casually, or for longer than 10 to 14 days, as resistance quickly develops to this agent. Rifampin is also a well-known inducer of several cytochrome p450 isoenzymes and therefore has a high potential for drug interactions. Failure of a patient to respond to antimicrobial therapy after 72 hours of therapy should prompt either a switch to alternate antimicrobial therapy or reevaluation of the patient (see Table 4). When a change in antibiotic therapy is made, the clinician should consider the limitations in coverage of the initial agent. Patients who have received effective antibiotic therapy and continue to be symptomatic may need further evaluation. A CT scan, fiberoptic endoscopy or sinus aspiration and culture may be necessary. Recommendations for initial therapy for children with mild disease and who have not received antibiotics in the previous 4 to 6 weeks include the following: high-dose amoxicillin/clavulanate (90 mg/6.4 mg per kg per day), amoxicillin (90 mg/kg per day), cefpodoxime proxetil, cefuroxime axetil, or cefdinir. TMP/SMX, azithromycin, clarithromycin, or erythromycin is recommended if the patient has a history of immediate Type I hypersensitivity reaction to β-lactams. These antibiotics have limited effectiveness against the major pathogens of ABRS and bacterial failure of 20% to 25% is possible. The clinician should differentiate an immediate hypersensitivity reaction from other less dangerous side effects. Children with immediate hypersensitivity reactions to β-lactams may need: desensitization, sinus cultures, or other ancillary procedures and studies. Children with other types of reactions and side effects may tolerate one specific β-lactam, but not another. Failure to respond to antimicrobial therapy after 72 hours should prompt either a switch to alternate antimicrobial therapy or reevaluation of the patient (see Table 5).When a change in antibiotic therapy is made, the clinician should consider the limitations in coverage of the initial agent. The recommended initial therapy for children with mild disease who have received antibiotics in the previous 4 to 6 weeks or children with moderate disease is high-dose amoxicillin/clavulanate (90 mg/6.4 mg per kg per day). Cefpodoxime proxetil, cefuroxime axetil, or cefdinir may be used if there is a penicillin allergy (eg, penicillin rash); in such instances, cefdinir is preferred because of high patient acceptance. TMP/SMX, azithromycin, clarithromycin, or erythromycin is recommended if the patient is β-lactam allergic, but these do not provide optimal coverage. Clindamycin is appropriate if S pneumoniae is identified as a pathogen. Ceftriaxone (parenteral, 50 mg/kg per day for 5 days) or combination therapy with adequate gram-positive and -negative coverage may also be considered. Examples of appropriate regimens of combination therapy include high-dose amoxicillin or clindamycin plus cefixime, or high-dose amoxicillin or clindamycin plus rifampin. The clinical effectiveness of ceftriaxone and these combinations for ABRS is unproven; the panel considers these reasonable therapeutic options based on spectrum of activity and on data extrapolated from acute otitis media studies. Rifampin should not be used as monotherapy, casually, or for longer than 10 to 14 days as resistance quickly develops to this agent. Failure to respond to antimicrobial therapy after 72 hours of therapy should prompt either a switch to alternate antimicrobial therapy or reevaluation of the patient (see Table 5). When a change in antibiotic therapy is made, the clinician should consider the limitations in coverage of the initial agent. Patients who have received effective antibiotic therapy and continue to be symptomatic may need further evaluation. A CT scan, fiberoptic endoscopy or sinus aspiration and culture may be necessary.

                Author and article information

                Emerg Infect Dis
                Emerging Infect. Dis
                Emerging Infectious Diseases
                Centers for Disease Control and Prevention
                June 2005
                : 11
                : 6
                : 985-987
                [* ]Christ Hospital, Jersey City, New Jersey, USA
                [* ]Veterans Affairs Medical Center and Duke University Medical Center, Durham, North Carolina, USA
                Author notes
                Address for correspondence: Spartaco Bellomo, Christ Hospital, Division of Infectious Diseases, 142 Palisade Ave, Jersey City, NJ 07306, USA; fax: 201-653-6697; email: idbells@
                Address for correspondence: Richard Frothingham, Duke Human Vaccine Institute, Duke University Medical Center Box 3258, Room 124 SORF, LaSalle St Extension, Durham, NC 27710, USA; fax: 919-684-4288; email: richard.frothingham@
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