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After completing this continuing education article, the pharmacist should be able to:
Respiratory tract infections represent a significant area for improving antibiotic use in the community setting. The majority of antibiotics prescribed to adults in the United States are for acute respiratory tract infections, and a large proportion may be unnecessary. The high use of some antibiotics has contributed to the emergence and spread of resistant organisms in the community-namely, Streptococcus pneumoniae.1 The Centers for Disease Control and Prevention (CDC) convened a group of experts to develop evidence-based guidelines for the judicious use of antibiotics in the treatment of respiratory tract infections in adults. In addition, the Infectious Diseases Society of America (IDSA), the American Thoracic Society (ATS), and the CDC have published recommendations for the treatment of CAP in adults. The purpose of this article is to summarize these recommendations, outline the most appropriate candidates for antimicrobial therapy, and discuss the potential role of the community pharmacist in promoting antibiotic stewardship.
The pneumococcus is the most common bacterial cause of respiratory tract infections, including CAP, bacterial sinusitis, and otitis media.2 Penicillin resistance in S pneumoniae has increased in an epidemic manner over the past 10 years. A recent study2 evaluated the prevalence of multidrug-resistant pneumococci in the United States. This study revealed that 24% of isolates were resistant to penicillin and were also more likely to be resistant to other drugs. During the period from 1995 to 1998, the proportion of isolates that were resistant to 3 or more drugs increased from 9% to 14%.2 In addition, a Canadian study reported increased resistance of S pneumoniae to the fluoroquinolones as a result of an increase in the use of these agents.3 Resistance to the macrolides among S pneumoniae has increased in the United States as well. Macrolide resistance increased to 20% in 1999 as a result of a 13% increase in macrolide use from 1993 to 1999.4 As a result, the prevalence of drug-resistant S pneumoniae serves as the driving force in combating resistance in the community.
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Many studies have demonstrated a correlation between the use of antibiotics and the development of resistance.5 Approximately 75% of all antibiotic prescriptions written in the outpatient setting in the United States are for the treatment of respiratory tract infections, many of which are of a viral etiology.6 This level of inappropriate prescribing is driven by many factors (Table 1).6 For example, many physicians believe that not prescribing antibiotics will lead to patient dissatisfaction with care. In a study of adults seeking care for acute respiratory illness, however, the quality of the interaction between caregiver and patient rather than a prescription was the most important determinant of patient satisfaction.7 In addition to dissatisfaction, physicians also report patient pressure and insufficient time to educate patients about the lack of need for antibiotics as reasons for prescribing antibiotics for respiratory tract infections.8
Sinusitis is defined as inflammation of the mucosa of the paranasal sinuses. Because it is often accompanied by inflammation of the contiguous nasal mucosa, rhinosinusitis has become the more appropriate terminology. Rhinosinusitis is among the 10 most common diagnoses in ambulatory practice and is the fifth most common diagnosis for which antibiotics are prescribed.9 Primary care physicians tend to think of rhinosinusitis as bacterial in origin, and they prescribe antibiotics in up to 98% of cases.10
Acute rhinosinusitis is defined by duration of symptoms of less than 4 weeks. It is usually a secondary infection resulting from obstruction caused by a preceding viral infection.11 Less than 2% of these viral infections progress to a secondary bacterial rhinosinusitis.12 When bacteria are isolated, S pneumoniae and Haemophilus influenzae are the most common bacterial causes of rhinosinusitis.13
Bacterial rhinosinusitis and viral sinusitis are clinically indistinguishable. The result is frequent inaccurate diagnosis or overdiagnosis of a bacterial etiology. Clinical features of both viral and bacterial rhinosinusitis include sneezing, nasal discharge, rhinorrhea, nasal obstruction, facial pressure, and headache. Physician classification of patients likely to have a bacterial cause is correct in only 50% of cases.14
Duration of illness has been suggested as a potential factor to distinguish between the etiologies. In studies of patients with viral rhinosinusitis, only 25% of patients had symptoms lasting more than 2 weeks.15 In fact, most were improved within 7 to 10 days. In bacterial rhinosinusitis, only a small portion of patients have symptoms that last less than 7 days. Therefore, patients with duration of symptoms of less than 7 days are unlikely to have acute bacterial rhinosinusitis.
Several studies have attempted to identify helpful signs and symptoms to distinguish between the 2 syndromes. Unfortunately, no single sign or symptom had a strong predictive value in differentiation of infectious etiology. Yet, 4 findings have been associated with an increased likeli-hood of bacterial infection: (1) history of purulent nasal discharge with unilateral predominant, (2) history of facial pain with unilateral predominance, (3) history of bilateral purulent nasal discharge, and (4) pus in the nasal cavity upon examination.16 When at least 2 findings are present, up to 85% of patients have bacterial sinusitis. In contrast, if no findings or 1 is present, fewer than 10% have a bacterial etiology.
The diagnostic standard for acute rhinosinusitis is sinus aspiration of purulent secretions, but this invasive procedure is rarely performed in the outpatient setting. Sinus puncture is usually reserved for complicated cases of acute rhinosinusitis. Diagnostic imaging of the sinuses, including plain radiography or computed tomography scanning, have limited value in the routine diagnosis of acute bacterial rhinosinusitis because they lack specificity and cannot distinguish viral from bacterial origins.
Supportive care is the preferred initial treatment for patients with mild symptoms.17-19 Appropriate doses of analgesics and antipyretics should be recommended. In addition, irrigation of the nasal cavity with sodium chloride may result in dramatic relief of pain and prevent subsequent mucosal damage. Supportive care also may consist of decongestants, antihistamines, and corticosteroids. These ancillary therapies have not been uniformly studied, and, as a result, the data remain inconclusive as to the precise benefit of supportive care. The use of decongestants may help relieve nasal congestion. Antihistamines have not been proven effective and theoretically may be harmful, secondary to their anticholinergic action. Corticosteroids have been studied, with variable results. Given their delayed onset of effect, the acute process will likely be resolved before their beneficial effects are seen.
Antibiotic treatment should be reserved for patients with moderate to severe signs and symptoms lasting >7 days, including facial or tooth pain and purulent secretions. Antibiotic treatment has been shown to result in successful eradication of bacteria from the sinuses, although the clinical benefit of eradication remains unproven. A pair of recent meta-analyses have concluded that, although antibiotics are statistically more effective than placebo in reducing symptoms, most placebo-treated patients improve without antibiotic therapy.19 In fact, up to 40% of patients will improve without antimicrobial therapy.
According to the expert panel convened by the CDC,17 patients who meet the criteria for antibiotics do not necessarily require treatment with a newer agent. These newer and broadspectrum agents are not substantially more effective than narrow agents for acute maxillary sinusitis.20 The panel's evidence-based recommendations support amoxicillin as the initial treatment of choice. Treatment duration should be 10 days. If the patient has a t-lactam allergy, trimethoprim/sulfamethoxazole or doxycycline is a suitable alternative. Likewise, the Agency for Health Care Policy and Research guidelines18 support the use of amoxicillin or trimethoprim/sulfamethoxazole as a first-line agent. They suggest that the current evidence does not support the use of newer antibiotics for treating acute bacterial rhinosinusitis.
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In contrast, the Sinus and Allergy Partnership19 divides patients into 2 categories by severity of disease: mild and moderate. In addition, prior antibiotic use is taken into consideration as a major risk factor for the development of a resistant infection, and patients are stratified according to antibiotic exposure in the previous 4 to 6 weeks. For patients with mild disease and no previous antibiotic use, amoxicillin/clavulanate, amoxicillin (1.5-3.5 g/day), cefpodoxime proxetil, or cefuroxime axetil is recommended. Trimethoprim/sulfamethoxazole, doxycycline, and the macrolides are typically not recommended unless the patient has a true t-lactam allergy because of their limited effectiveness. For patients with mild disease and previous exposure to antibiotics or patients with moderate disease and no prior antibiotic treatment, amoxicillin/clavulanate, high-dose amoxicillin (3-3.5 g/day), cefpodoxime proxetil, or cefuroxime axetil is a suggested regimen. Lastly, for patients with moderate disease who have received previous antibiotic treatment, amoxicillin/clavulanate or a fluoroquinolone such as levofloxacin, gatifloxacin, or moxifloxacin is recommended. Table 2 provides a suggested list of regimens for the treatment of acute bacterial rhinosinusitis, with predicted rates of efficacy.
Acute pharyngitis is one of the most common illnesses for which patients visit primary care physicians, accounting for 1% to 2% of all visits.21 The illness occurs predominantly in schoolaged children, aged 5 to 15 years. In a healthy adult, the sore throat, fever, and malaise are often self-limited and occur without complications.
Viruses are the most common cause of acute pharyngitis; however, up to 15% of adult cases are caused by Group A streptococcus.22 Group A streptococcal pharyngitis is the only form of the disease for which antibiotic therapy is indicated. Historically, the purpose of treatment was to prevent poststreptococcal sequelae such as rheumatic fever, acute glomerulonephritis, and suppurative complications. Although early data supported the efficacy of penicillin in preventing rheumatic fever, the incidence of rheumatic fever during this time was substantially greater than it is today. As a result, the true benefit of treatment today is unknown.23 Glomerulonephritis is a rare complication even without antibiotic therapy.24 In addition, there is no evidence that antibiotics are effective in preventing the complication. Clinical trials continue to support the use of antibiotics to prevent peritonsillar abscess, although the incidence of such complications also is low.25
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Characteristic clinical findings of streptococcal pharyngitis are summarized in Table 3.26 The presence of findings such as tonsillopharyngeal exudates and cervical lymphadenitis increases the likelihood that the causative agent is group A streptococcus.27
Diagnosis of streptococcal pharyngitis remains controversial because the best diagnostic standard has not been identified and no current diagnostic modality provides results in a timely manner to aid the decision regarding antibiotic treatment. Patients with acute pharyngitis should be tested for the presence of group A streptococci by means of either a throat culture or a rapid test for group A streptococcal antigen. The throat culture remains the gold standard for the diagnosis of streptococcal pharyngitis. Unfortunately, the results are not typically reported for 24 to 48 hours and do not differentiate between the carrier state and acute infection. In patients in whom the clinical suspicion for streptococcal pharyngitis is high, it is feasible to initiate therapy while awaiting culture results. The rapid antigen test, which can confirm the presence of group A streptococcal carbohydrate antigen on a throat swab, provides results in a matter of minutes. Like the throat culture, however, it cannot distinguish between carrier state and acute infection. In addition, although it is highly specific, its sensitivity is less than that of the throat culture (80% to 90%). Therefore, advisory committees have recommended that negative throat swabs be confirmed with a conventional throat culture.28 Both the value and necessity of this confirmatory process remain uncertain.
Clinical criteria such as the Centor criteria are the most reliable predictors of streptococcal pharyngitis.29 These include tonsillar exudates, cervical lympadenopathy, absence of cough, and history of fever. Several studies have indicated that the presence of 3 or more criteria has a positive predictive value of up to 60%.30
The objectives of antimicrobial therapy for group A streptococcal pharyngitis are to prevent suppurative complications and rheumatic fever and to decrease infectivity as well as symptoms.31 There is no firm evidence that treatment will prevent the development of acute glomerulonephritis. Treatment of group A streptococcal pharyngitis today consists of treating to prevent already rare complications of the infection and decreasing symptomatology by 1 to 2 days.
An appropriate treatment strategy in adults is to limit the administration of antibiotics to the small proportion of patients with an increased likelihood of streptococcal pharyngitis. Empiric therapy should be initiated for patients who meet at least 3 of the 4 clinical criteria. Patients with a subsequent positive throat culture should continue antibiotic treatment, whereas a negative throat culture should prompt the discontinuation of empiric therapy. Penicillin remains the drug of choice for the treatment of group A streptococcal pharyngitis because of its sustained efficacy, narrow spectrum, safety, and low cost. A full 10-day course is recommended to ensure adequate eradication of organisms from the pharynx. For patients with an allergy to penicillin, erythromycin or azithromycin is a suitable alternative. Eradication rates with 5 days of azithromycin are similar to those with 10 days of penicillin.28 The macrolides, however, remain agents of second choice because of increased cost and potential negative effects on resistance patterns. Streptococcal resistance to macrolides has developed more rapidly, in comparison with penicillin. Table 4 summarizes common treatment regimens for streptococcal pharyngitis.28,31
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Acute bronchitis is defined by an acute respiratory infection in which cough, with or without phlegm, is the predominant feature.32 In 1997, adults in the United States made more than 10 million office visits for bronchitis.33 As a result, acute bronchitis ranks among the top 10 conditions that necessitate a physician visit. Acute upper respiratory tract infection accounted for approximately 70% of diagnoses in adults presenting with a chief complaint of cough.34 Acute bronchitis is further defined as an acute cough illness lasting less than 3 weeks.35 This discussion of acute bronchitis will focus on healthy immunocompetent adults without chronic lung disease.
In addition to cough, clinical features such as sore throat and rhinorrhea are used to distinguish bronchitis from other respiratory tract infections.36 The absence of tachycardia, tachypnea, fever, or chest examination suggesting consolidation significantly decreases the likelihood of pneumonia as well as the need for diagnostic imaging.37 The primary objective for patients with acute cough illness should be to exclude the presence of pneumonia.38
More than 90% of cases of acute bronchitis have a nonbacterial cause.38 Noninfectious causes such as asthma exacerbation or inhalation of irritant fumes also must be considered. Respiratory viruses, particularly influenza, cause the large majority of cases of acute bronchitis. No microbiologic evidence indicates that S pneumoniae, H influenzae, or Moraxella catarrhalis causes acute bronchitis in adults without underlying disease.38
Routine antimicrobial treatment of acute bronchitis is not recommended.38 Randomized, controlled trials have failed to support a role for antibiotic therapy.39,40 Antibiotics appear to have no impact on duration of illness, ability to return to normal activity, and prevention of complications.
Supportive care should be offered to all patients with acute bronchitis. The focus should be on identifying and treating the symptoms that are most bothersome to each individual patient. Albuterol has demonstrated a consistent benefit in clinical trials, decreasing both the duration and the severity of cough.41 Additional options include cough suppressants such as dextromethorphan and codeine.
Pneumonia is an inflammation of the lung parenchyma caused by acute infection. It is the sixth leading cause of death and the number-1 cause of death due to infectious diseases in the United States.42,43 It is estimated that 2 million to 3 million cases of CAP occur annually, resulting in 10 million physician visits, 500,000 hospitalizations, and 45,000 deaths.44
Nearly all patients with pneumonia have fever, cough (with or without sputum production), and a physical examination and chest radiograph that indicate consolidation in 1 or more areas of the lung.45 In addition, patients may complain of pleuritic (knife-like) chest pain or be hypoxic and tachypneic. Upon physical examination and auscultation of the chest, decreased breath sounds, dullness on chest percussion, vowel tone changes (E to A changes, also called egophony), chest splinting, and an inspiratory lag are highly suggestive of a lung consolidation. All of these signs are suggestive of a pneumonic process and usually are present on the affected lung.
Historically, clinicians have attempted to classify pneumonia as "typical" or "atypical." This categorization originated from the presumption that the presenting symptoms of pneumonia secondary to pathogens such as S pneumoniae, H influenzae, Staphylococcus aureus, and enteric gram-negative bacteria ("typical") is different from that observed for Mycoplasma spp, Legionella spp, and Chlamydia spp ("atypical"). The atypical pathogens of CAP are theoretically associated with an atypical clinical presentation, including subacute onset, nonproductive cough, extrapulmonary manifestations, and a chest radiograph that is characteristically worse than the patient's clinical appearance would suggest. However, S pneumoniae and viruses have been documented to cause a syndrome indistinguishable from that caused by M pneumoniae. Consequently, reliance on the presence of specific symptoms in the etiology of pneumonia may be unreliable. This diagnostic difficulty commonly results in the empiric use of antibacterials in the treatment of pneumonia.
S pneumoniae is the most common cause of pneumonia in all age groups, identified in 25% to 60% of all community-acquired bacterial pneumonias.45 Other common bacterial pathogens include H influenzae (3%-10%), S aureus (3%-5%), and gram-negative bacilli (3%-10%). Legionella are more common in middle-aged and elderly adults and have the highest mortality rate of the atypical pathogens. Mycoplasma (also referred to as "walking pneumonia") are more common in young adults and carry virtually no mortality.
Ideally and if possible, sputum should be collected by having the patient cough and expectorate lower respiratory tract secretions in efforts to identify the causative agent. Unfortunately, the causative organism is established in only 30% to 50% of cases.
Although a number of tests are utilized to document pneumonia, a chest radiograph most clearly distinguishes pneumonia from other disease states. Congestive heart failure, pulmonary embolism, and other diseases may mimic the signs and symptoms of pneumonia. In the majority of cases, a chest x-ray is the one test that differentiates between acute bronchitis, an infection that does not require antibiotics, and pneumonia, one that widely benefits from antimicrobial therapy.
Initial antimicrobial therapy is largely empirical and should be guided by the results of the sputum Gram stain, patient age, prior medical history, concomitant diseases, prior place of residence, and clinical signs and symptoms. If no sputum is available for Gram stain, antibiotics active against the most probable bacterial pathogens are selected.
For treatment of CAP in an ambulatory setting, the IDSA guidelines44 recommend doxycycline, a macrolide, or an antipneumococcal fluoroquinolone as the preferred agent because these agents have activity against the most likely pathogens in this setting (S pneumoniae, M pneumoniae, and C pneumoniae). Currently available antipneumococcal fluoroquinolones include levofloxacin, gatifloxacin, and moxifloxacin. Since the comparison of spectrum of activity yields only minor differences, the selection of the most appropriate agent typically relates to toxicity profiles and cost.
Serious hyper- and hypoglycemic episodes have been reported in patients with type 2 diabetes receiving gatifloxacin. 46 Likewise, hyperglycemic episodes have also occurred in patients without a history of type 2 diabetes.46 Careful monitoring of blood glucose is recommended when gatifloxacin is administered to patients with diabetes or patients at risk for hyperglycemia, such as elderly patients who may have unrecognized diabetes, patients with age-related decrease in renal function, or patients taking concomitant medications associated with hyperglycemia.46
Moxifloxacin was reported to prolong the QT interval approximately 3 to 4 milliseconds and thus should be used with caution in patients receiving Class IA or Class III antiarrhythmics or patients with history of proarrhythmic conditions, such as recent hypokalemia or myocardial ischemia.47 In addition, moxifloxacin has in vitro activity against anaerobic organisms and may be useful as a single agent in the treatment of patients with aspiration pneumonia or other mixed infections.
The CDC working group48 on drugresistant S pneumoniae suggests that penicillin-resistant S pneumoniae isolates are uncommon, and activity against such organisms is unnecessary for empiric treatment. Their recommendations for first-line therapy of CAP include a macrolide, doxycycline, or an oral ¥â-lactam such as cefuroxime, amoxicillin, or amoxicillin/clavulanate. The CDC recommends reserving the use of fluoroquinolones for the treatment of patients with gram-negative pathogens, patients with ¥â-lactam allergy, or patients with penicillinresistant pneumococcal pneumonia.
Lastly, the American Thoracic Society (ATS) guidelines49 separate CAP patients into 2 categories: (1) patients with risk factors for drug-resistant S pneumoniae, gram-negative infections or aspiration or with cardiopulmonary disease, and (2) patients without cardiopulmonary disease or without any of the aforementioned risk factors for infection. In patients without risk factors or cardiopulmonary disease, the ATS recognizes that fluoroquinolone use in this population may be unnecessary and recommends treatment with a macrolide or doxycycline. For more complex patients with risk factors or cardiopulmonary disease, oral therapy with a combination of an oral t-lactam (cefpodoxime, cefuroxime, amoxicillin, amoxicillin/clavulanic acid) and a macrolide or monotherapy with a fluoroquinolone may be utilized.
Although resistance rates are increasing, the clinical impact of pneumonia caused by drug-resistant S pneumoniae is controversial. Much of the confusion over this issue is related to the designation of in vitro pneumococcal resistance to penicillin. The National Committee for Clinical Laboratory Standards currently designates pneumococcal isolates as susceptible if the minimum inhibitory concentration (MIC) is ¡Â0.06 mcg/mL, intermediate if the MIC value falls between 0.1 and 1.0 mcg/mL, and resistant if the MIC is ¡Ã2.0 mcg/mL.50 These current definitions are based on levels achieved in cerebrospinal fluid in cases of meningitis. Much higher levels, however, can be attained in both the blood and the lung.
Therefore, although these categories appear to have clinical relevance for some agents used to treat otitis media and meningitis, they may be inappropriate for guiding the treatment of pneumonia. Despite the report of treatment failures in otitis media and meningitis, comparative studies of pneumococcal pneumonia indicate that pneumococcal resistance does not have a deleterious impact on treatment outcome. Available data show that mortality in CAP is adversely affected by drug-resistant pneumococci when MIC ¡Ã4.51
Preventing resistance and improving the use of antibiotics involves the participation of many health care professionals, including pharmacists. The pharmacist serves as the link between the physician and the patient and can promote both prescriber and patient change, as well as vaccination.
Pharmacists can play a significant role in promoting prescriber change through education, decision support and treatment recommendations, and audit and feedback mechanisms.52
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Prescriber Education. Academic detailing provides prescribers with clinical information and has been shown to alter decision making, especially when delivered by a fellow colleague. Studies have shown that provider education efforts are most effective when they are viewed as assistance rather than restriction.53 Academic detailing or educational visits should begin with determining the prescriber's baseline knowledge and scope of practice. Education directed toward small groups appears to be most beneficial, when compared with mass mailing. The program's success is often largely dependent on the degree of active participation by the prescribers. Table 5 includes important techniques in delivering successful academic detailing.6
Decision Support and Treatment Recommendations. Integrating pharmacy data, such as medication history and concomitant disease states, the pharmacist can help in the decisionmaking process as well. He or she is able to promote prescriber change by providing patient-specific recommendations regarding drug regimen, dose, and duration of therapy. In addition, the pharmacist is able to identify potential drug interactions among concurrent drug therapies.
Audit and Feedback. An audit or drug use evaluation generally involves a review of the prescriber's practice for a given disease state. Feedback consists of a report on the practice activities when compared with guidelines or treatment strategies. The success of audit and feedback relies on the prescriber's willingness to accept the feedback and to show interest in improving his or her practices.
Pharmacists serve as the critical link in communicating information about health and treatment to patients.54 The American Society of Health-System Pharmacists has published guidelines for patient education and counseling by pharmacists.55 These guidelines include establishing a relationship with the patient, identifying the patient's knowledge about current health and medication needs, and providing information, both orally and visually.
Education to promote patient change in limiting antibiotic resistance54 should include explaining the consequences of unnecessary antibiotics, discussing viral infections and the ineffectiveness of antibiotics for such illnesses, and encouraging and recommending supportive treatment. The CDC also has suggested providing patients with written information listing symptomatic therapy for upper respiratory tract infections that do not require antibiotics.54
The pharmacist also can promote change by recommending or even administering vaccinations. With the increasing prevalence of S pneumoniae infections, the pneumococcal vaccine is an important method of preventing disease in high-risk populations. It is recommended for all persons over the age of 65 and for people aged 2 to 64 with a specific risk for invasive pneumococcal disease, including chronic cardiovascular or pulmonary disease, diabetes, functional asplenia, compromised immune system, and alcoholism or chronic liver disease.56
Despite the fact that many organizations recommend vaccination, the vaccine remains substantially underadministered. In the outpatient setting, vaccination rates have been improved through reminder and education, although 70% of the high-risk patients were not vaccinated.
Pharmacists have become increasingly involved in immunizing adults against both influenza and pneumococcal disease. In addition to promoting vaccination through education, pharmacists are expanding their responsibility to include administering the vaccines in some states. As a result, pharmacy schools across the country are preparing future pharmacists not only to safely and effectively provide medications, but also to administer immunizations appropriately.
Antibiotic resistance remains an increasing problem in the community setting. Using antibiotics rationally is the most basic of methods in combating this resistance. Large organizations have provided recommendations for the appropriate use of antibiotics in the treatment of respiratory tract infections in adults. Based on their guidelines, the practitioner can identify the most appropriate candidates for antibiotics and choose the most appropriate regimen as well. Pharmacists can serve as the critical link between physicians and patients by promoting prescriber and patient change as well as promoting vaccination.
Assistant Professor of Clinical Pharmacy, Temple University School of Pharmacy