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Acute Pharyngitis: The Case for Empiric Antimicrobial Therapy
EDITORIAL
Editorial
Acute Pharyngitis: The Case for Empiric Antimicrobial Therapy Steven M Green, MD, FACEP Department of Emergency Medicine Lorna Linda University School of Medicine Lorna Linda, California Copyright © by the American College of Emergency Physicians.
404
Acute Pharyngitis: The Case for Empiric Antimicrobial Therapy See related article, p 390. [Green SM: Acute pharyngitis: The case for empiric antimicrobial therapy. Ann Emerg Med March 1995;25:404-406.] On a daily basis, emergency physicians evaluate minor infections (eg, otitis media, sinusitis) in which clinical examination cannot reliably distinguish bacterial and viral causes. Physician judgment is used to determine which patients have a reasonable risk of bacterial illness and should thus receive empiric antibiotics. Should pharyngitis be managed any differently? In this issue's review of group A streptococcal (GAS) tonsillopharyngitis, Dr Pichichero emphasizes the proven unreliability of clinical examination in distinguishing true GAS disease. Despite this diagnostic difficulty, a subset of patients at low risk for GAS can be clinically identified, particularly those with associated rhinorrhea, cough, or hoarseness and lacking fever, lymphadenitis, or tonsillar exudate. These patients are almost certainly experiencing viral illness, and antibiotics or diagnostic testing is unnecessary Patients lacking these "low-risk" features, however, do have a reasonable risk of GAS, and further intervention is warranted. Pichichero says that rapid GAS antigen testing can be used for these emergency department patients as "the definitive determiner for treatment." He discourages the alternative strategy of empiric therapy and describes it as less cost-effective. Accurate determination of cost-effectiveness requires a reliable assessment of diagnostic test sensitivity. This sensitivity, in tum, must be calculated relative to a reliable reference, a "gold standard." Although Pichichero asserts that the standard throat culture "remains the gold standard of diagnosis" for GAS disease, many authorities disagree with this premise. 1 - 10 In their recent detailed review of GAS pharyngitis, Kline and Runge 1 describe an increase in antistreptococcal antibodies (ASO titer)
ANNALS OF EMERGENCY MEDICINE
25:3
MARCH 1995
EDITORIAL
as "the standard definition of truly acute streptococcal pharyngitis." They note that significant ASO titer increases have been noted in 45% of patients with pharyngitis and negative throat cultures, suggesting that culture itself may be quite insensitive. Alternative methods such as tissue culture 11 •12 , multiple swabbed specimens4·5·10, optical immunoassay8 , and a special two-plate culture method 7 have been reported to increase the detection of GAS by up to 42% over that with standard culture. Thus, although the throat culture may be convenient and readily available, its utility as a reliable reference standard remains in serious question. Accordingly, depending on culture results to determine when antimicrobial agents are prescribed potentially leaves many truly diseased patients untreated. Pichichero's abstract gives an overly optimistic appraisal of antigen testing: "When used appropriately [emphasis added], it is sensitive (79% to 88%) in detecting GAS-infected patients .... " This is inconsistent with Table 3 of his review, which reports studies with sensitivities as low as 45%. Pichichero excludes mention of these studies from his abstract, postulating that the observed lower sensitivities may have resulted from "short cuts and lack of attention to detail." Two of the excluded studies reporting dismal45% to 55% sensitivities were ED-based 13 ·14 and may thus represent the most accurate depiction of this test's reliability in our unique practice setting. This same table omits the journal of the American Medical Association studies of Wegner and colleagues 7 and Kellogg and Manzella 4, which noted sensitivities of 31% to 50% (office-based) and 63% (hospital-based), respectively. Because of the unacceptably high false-negative rates noted in multiple studies, essentially all authorities have concluded that a negative antigen test requires subsequent confirmation with a culture. 1 A· 6·13 ·15 This limitation of antigen testing is extremely important. Clinicians must realize that a negative antigen test alone cannot reliably rule out GAS disease. In assessment of cost-effectiveness, it may be misleading to compare institutional costs instead of patient charges. Most EDs are not yet dominated by managed care, and the actual patient charge continues to be of greater interest to both our patients and their insurance companies. At my hospital, for example, 14 complete courses of penicillin can be purchased for the charge of a single antigen test with confirming culture (penicillin, $5.65; Directigen®, $39; single-plate throat culture, $42). Cost-effectiveness must be defined and interpreted within specific clinical settings.
MARCII1995
25:3
ANNALS OF EMERGENCY MEDICINE
After summarizing several financial analyses, Pichichero concludes that empiric therapy is less cost-effective than antigen or culture-guided therapy in most circumstances. However, he does not refer to the only such analysis performed in the ED setting 16 , which concluded the opposite: that empiric therapy was more cost-effective in patients clinically judged to be at intermediate to high risk for GAS infection. Analyzing cost-effectiveness requires making assumptions about the relative costs and risks associated with various treatment strategies. The authors of the GAS cost-effectiveness reports summarized by Pichichero admit that many of their assumptions do not have a convincing scientific basis and that relatively small errors in these conjectures could lead to quite opposite conclusions. According to one author, "Because there are uncertainties about the data used for this study, whether the analysis should have been done at all could be questioned. "5 The first of these analyses, in 1977 by Tompkins and colleagues 5, found that empiric therapy was most cost -effective if the throat culture positivity rate was 20% or greater (uncommon) and that cultureguided therapy was more appropriate when the rate was 5% to 20% (common). The most recent of these analyses, in 1990 by Lieu and colleagues 17 , concluded, 'The strategy of treating all patients prevents the most streptococcal complications and has the least short term dollar cost per case of disease prevented." However, it was deemed the most expensive strategy overall because of the increased incidence of unanticipated allergic reactions. The distinction between assumed true cost and actual patient charge is pivotal in these analyses. These reports 5·17 used costs for their analyses, with assumed values for single-plate throat culture and antigen test of $2 to $5 and $3, respectively. These costs differ by an order of magnitude from charges at my hospital, where patients are billed $4 2 and $39 for these tests, respectively. Although these estimates of true cost may be of interest to govern.rnent health care planners and HMO executives, they are certainly inapplicable to typical fee. for-service EDs. If Drs Tompkins and Lieu were to repeat their analyses and base them on current ED charges, their conclusions regarding cost-effectiveness might be reversed. Finally, these cost-effectiveness analyses fail to factor in other important issues such as ED throughput time, rate of symptomatic recovery, and the difficulties of follow-up contact. The reliability of longitudinal care in the ED varies substantially from setting to setting. Many EDs lack
405
EDITORIAL
funding for the secretarial and nursing time required to methodically and consistently follow up delayed testing results such as throat cultures, Pap smears, and HIV tests. Tracking down patients without telephones or permanent addresses can be burdensome or impossible. In typical urban EDs, physicians have only one chance to intervene, for many patients, before these individuals are effectively lost to the system. If physicians judge that follow-up of throat cultures is unreliable in their specific ED setting, then they are left with only two choices for the patient clinically deemed at risk for GAS infection: antigen testing or empiric treatment. Because the former is variably sensitive, incurs high patient charges, and delays disposition by approximately l hour, the latter would appear to be a reasonable alternative. What do our patients want? I believe that, allowed an informed decision, most individuals with pharyngitis would opt for the treatment alternative that gets them out of the ED the fastest, most rapidly improves their symptoms, has the lowest ED charge, most effectively limits their period of contagion, and has the lowest risk of suppurative or rheumatic complications. It is unlikely that a slight increase in the already trivial risk of unanticipated allergic reaction would dissuade a patient from these tangible benefits of empiric therapy Emergency physicians should carefully consider the logistic and economic realities of their specific practice settings when choosing treatment strategies. In many EDs, empiric antimicrobial therapy for patients at reasonable risk of GAS pharyngitis would appear to be both cost-effective and medically appropriate.
10. Roddey OF, Clegg HW, Clardy LT, et al: Comparison of a latex agglutination test and four culture methods for identification of group A streptococci in a pediatric office laboratory. J Pediatr 1986;108:347-351. 11. Brook I, Yocum P, Shah K: Surface vs core-tonsillar aerobic and anaerobic flora in recurrent tonsillitis. JAMA 1980;244:1696-1698. 12. Rosen G, Samuel J, Vered 1: Surface tonsillar microflora versus deep tonsillar microflora in recurrent acute tonsillitis. J Laryngol Dtol1 977;91 :911-912.
13. Lieu TA, Fleisher GR, Schwartz JS: Clinical performance and effect on treatment rates of latex agglutination testing for streptococcal pharyngitis in an emergency department. Pediatr Infect Dis J 1986;5:655-659. 14. Lieu TA, Fleisher GR. Schwartz JS: Clinical evaluation of a latex agglutination test for streptococcal pharyngitis: Performance and impact on treatment rates. Pediatr Infect Dis 1988;7:847-854. 15. Pichichero ME, Disney FA, Green JL, et al: Comparative reliability of clinical, culture, and antigen detection methods for the diagnosis of group A beta-hemolytic streptococcal tonsillopharyngitis. Pediatr Ann 1992;21 :798-805. 16. Hedges JR. Lowe RA: Streptococcal pharyngitis in the emergency department: Analysis of therapeutic strategies. Am J Emerg Med 1986;4:1 07:115. 17. Lieu TA, Fleisher GR. Schwartz JS: Cost-effectiveness of rapid latex agglutination testing and throat culture for streptococcal pharyngitis. Pediatrics 1990;85246-256.
Reprint no. 47/1/63042 Address for reprints: Steven M Green, MD, FACEP Lama Linda University Medical Center Emergency Medicine Residency Program A-1 08 11234 Anderson Street Lama linda, California 92354 909-824-4085 Fax 909-478-4121
REFERENCES 1. Kline JA. Runge JW: Streptococcal pharyngitis: A review of pathophysiology, diagnosis, and management. J Emerg Med1994;12:665-680. 2. Dajani AS, Bisno AL, Chung KJ, et al: Prevention of rheumatic fever. Circulation 1988;78:1 0821086. 3. Taylor RB, Werman HA, Rund DA: Journal club: Streptococcal pharyngitis: Emerging concepts. Am J Emerg Med1988;6:306-311. 4. Kellogg JA, Manzella JP: Detection of group Astreptococci in the laboratory or physician's office. JAMA 1986;255:2638-2642. 5. Tompkins RK, Burnes DC, Cable WE: An analysis of the cost- effectiveness of pharyngitis management and acute rheumatic fever prevention. Ann Intern Med 1977;86:481-492. 6. Vukmir RB: Adult and pediatric pharyngitis: A review. J Emerg Med 1992;1 0:607-616. 7. Wegner DL, Witte DL, Schrantz RD: Insensitivity of rapid antigen detection methods and single blood agar plate culture for diagnosing streptococcal pharyngitis. JAMA 1992;267:695-697. 8. Harbeck RJ, Teague J, Crossen GR, et al: Novel, rapid optical immunoassay technique for detection of group A streptococci from pharyngeal specimens: Comparison with standard culture methods. J Clin Microbiol1 993;31 :839-844. 9. Gerber MA, Randolph MF, Chanatry J, et al: Antigen detection test for streptococcal pharyngitis: Evaluation of sensitivity with respect to true infections. J Pediatr 1986;108:654-658.
406
ANNALS OF EMERGENCY MEDICINE
25:3
MARCH 1995
Editorial
Acute Pharyngitis: The Case for Empiric Antimicrobial Therapy Steven M Green, MD, FACEP Department of Emergency Medicine Lorna Linda University School of Medicine Lorna Linda, California Copyright © by the American College of Emergency Physicians.
404
Acute Pharyngitis: The Case for Empiric Antimicrobial Therapy See related article, p 390. [Green SM: Acute pharyngitis: The case for empiric antimicrobial therapy. Ann Emerg Med March 1995;25:404-406.] On a daily basis, emergency physicians evaluate minor infections (eg, otitis media, sinusitis) in which clinical examination cannot reliably distinguish bacterial and viral causes. Physician judgment is used to determine which patients have a reasonable risk of bacterial illness and should thus receive empiric antibiotics. Should pharyngitis be managed any differently? In this issue's review of group A streptococcal (GAS) tonsillopharyngitis, Dr Pichichero emphasizes the proven unreliability of clinical examination in distinguishing true GAS disease. Despite this diagnostic difficulty, a subset of patients at low risk for GAS can be clinically identified, particularly those with associated rhinorrhea, cough, or hoarseness and lacking fever, lymphadenitis, or tonsillar exudate. These patients are almost certainly experiencing viral illness, and antibiotics or diagnostic testing is unnecessary Patients lacking these "low-risk" features, however, do have a reasonable risk of GAS, and further intervention is warranted. Pichichero says that rapid GAS antigen testing can be used for these emergency department patients as "the definitive determiner for treatment." He discourages the alternative strategy of empiric therapy and describes it as less cost-effective. Accurate determination of cost-effectiveness requires a reliable assessment of diagnostic test sensitivity. This sensitivity, in tum, must be calculated relative to a reliable reference, a "gold standard." Although Pichichero asserts that the standard throat culture "remains the gold standard of diagnosis" for GAS disease, many authorities disagree with this premise. 1 - 10 In their recent detailed review of GAS pharyngitis, Kline and Runge 1 describe an increase in antistreptococcal antibodies (ASO titer)
ANNALS OF EMERGENCY MEDICINE
25:3
MARCH 1995
EDITORIAL
as "the standard definition of truly acute streptococcal pharyngitis." They note that significant ASO titer increases have been noted in 45% of patients with pharyngitis and negative throat cultures, suggesting that culture itself may be quite insensitive. Alternative methods such as tissue culture 11 •12 , multiple swabbed specimens4·5·10, optical immunoassay8 , and a special two-plate culture method 7 have been reported to increase the detection of GAS by up to 42% over that with standard culture. Thus, although the throat culture may be convenient and readily available, its utility as a reliable reference standard remains in serious question. Accordingly, depending on culture results to determine when antimicrobial agents are prescribed potentially leaves many truly diseased patients untreated. Pichichero's abstract gives an overly optimistic appraisal of antigen testing: "When used appropriately [emphasis added], it is sensitive (79% to 88%) in detecting GAS-infected patients .... " This is inconsistent with Table 3 of his review, which reports studies with sensitivities as low as 45%. Pichichero excludes mention of these studies from his abstract, postulating that the observed lower sensitivities may have resulted from "short cuts and lack of attention to detail." Two of the excluded studies reporting dismal45% to 55% sensitivities were ED-based 13 ·14 and may thus represent the most accurate depiction of this test's reliability in our unique practice setting. This same table omits the journal of the American Medical Association studies of Wegner and colleagues 7 and Kellogg and Manzella 4, which noted sensitivities of 31% to 50% (office-based) and 63% (hospital-based), respectively. Because of the unacceptably high false-negative rates noted in multiple studies, essentially all authorities have concluded that a negative antigen test requires subsequent confirmation with a culture. 1 A· 6·13 ·15 This limitation of antigen testing is extremely important. Clinicians must realize that a negative antigen test alone cannot reliably rule out GAS disease. In assessment of cost-effectiveness, it may be misleading to compare institutional costs instead of patient charges. Most EDs are not yet dominated by managed care, and the actual patient charge continues to be of greater interest to both our patients and their insurance companies. At my hospital, for example, 14 complete courses of penicillin can be purchased for the charge of a single antigen test with confirming culture (penicillin, $5.65; Directigen®, $39; single-plate throat culture, $42). Cost-effectiveness must be defined and interpreted within specific clinical settings.
MARCII1995
25:3
ANNALS OF EMERGENCY MEDICINE
After summarizing several financial analyses, Pichichero concludes that empiric therapy is less cost-effective than antigen or culture-guided therapy in most circumstances. However, he does not refer to the only such analysis performed in the ED setting 16 , which concluded the opposite: that empiric therapy was more cost-effective in patients clinically judged to be at intermediate to high risk for GAS infection. Analyzing cost-effectiveness requires making assumptions about the relative costs and risks associated with various treatment strategies. The authors of the GAS cost-effectiveness reports summarized by Pichichero admit that many of their assumptions do not have a convincing scientific basis and that relatively small errors in these conjectures could lead to quite opposite conclusions. According to one author, "Because there are uncertainties about the data used for this study, whether the analysis should have been done at all could be questioned. "5 The first of these analyses, in 1977 by Tompkins and colleagues 5, found that empiric therapy was most cost -effective if the throat culture positivity rate was 20% or greater (uncommon) and that cultureguided therapy was more appropriate when the rate was 5% to 20% (common). The most recent of these analyses, in 1990 by Lieu and colleagues 17 , concluded, 'The strategy of treating all patients prevents the most streptococcal complications and has the least short term dollar cost per case of disease prevented." However, it was deemed the most expensive strategy overall because of the increased incidence of unanticipated allergic reactions. The distinction between assumed true cost and actual patient charge is pivotal in these analyses. These reports 5·17 used costs for their analyses, with assumed values for single-plate throat culture and antigen test of $2 to $5 and $3, respectively. These costs differ by an order of magnitude from charges at my hospital, where patients are billed $4 2 and $39 for these tests, respectively. Although these estimates of true cost may be of interest to govern.rnent health care planners and HMO executives, they are certainly inapplicable to typical fee. for-service EDs. If Drs Tompkins and Lieu were to repeat their analyses and base them on current ED charges, their conclusions regarding cost-effectiveness might be reversed. Finally, these cost-effectiveness analyses fail to factor in other important issues such as ED throughput time, rate of symptomatic recovery, and the difficulties of follow-up contact. The reliability of longitudinal care in the ED varies substantially from setting to setting. Many EDs lack
405
EDITORIAL
funding for the secretarial and nursing time required to methodically and consistently follow up delayed testing results such as throat cultures, Pap smears, and HIV tests. Tracking down patients without telephones or permanent addresses can be burdensome or impossible. In typical urban EDs, physicians have only one chance to intervene, for many patients, before these individuals are effectively lost to the system. If physicians judge that follow-up of throat cultures is unreliable in their specific ED setting, then they are left with only two choices for the patient clinically deemed at risk for GAS infection: antigen testing or empiric treatment. Because the former is variably sensitive, incurs high patient charges, and delays disposition by approximately l hour, the latter would appear to be a reasonable alternative. What do our patients want? I believe that, allowed an informed decision, most individuals with pharyngitis would opt for the treatment alternative that gets them out of the ED the fastest, most rapidly improves their symptoms, has the lowest ED charge, most effectively limits their period of contagion, and has the lowest risk of suppurative or rheumatic complications. It is unlikely that a slight increase in the already trivial risk of unanticipated allergic reaction would dissuade a patient from these tangible benefits of empiric therapy Emergency physicians should carefully consider the logistic and economic realities of their specific practice settings when choosing treatment strategies. In many EDs, empiric antimicrobial therapy for patients at reasonable risk of GAS pharyngitis would appear to be both cost-effective and medically appropriate.
10. Roddey OF, Clegg HW, Clardy LT, et al: Comparison of a latex agglutination test and four culture methods for identification of group A streptococci in a pediatric office laboratory. J Pediatr 1986;108:347-351. 11. Brook I, Yocum P, Shah K: Surface vs core-tonsillar aerobic and anaerobic flora in recurrent tonsillitis. JAMA 1980;244:1696-1698. 12. Rosen G, Samuel J, Vered 1: Surface tonsillar microflora versus deep tonsillar microflora in recurrent acute tonsillitis. J Laryngol Dtol1 977;91 :911-912.
13. Lieu TA, Fleisher GR, Schwartz JS: Clinical performance and effect on treatment rates of latex agglutination testing for streptococcal pharyngitis in an emergency department. Pediatr Infect Dis J 1986;5:655-659. 14. Lieu TA, Fleisher GR. Schwartz JS: Clinical evaluation of a latex agglutination test for streptococcal pharyngitis: Performance and impact on treatment rates. Pediatr Infect Dis 1988;7:847-854. 15. Pichichero ME, Disney FA, Green JL, et al: Comparative reliability of clinical, culture, and antigen detection methods for the diagnosis of group A beta-hemolytic streptococcal tonsillopharyngitis. Pediatr Ann 1992;21 :798-805. 16. Hedges JR. Lowe RA: Streptococcal pharyngitis in the emergency department: Analysis of therapeutic strategies. Am J Emerg Med 1986;4:1 07:115. 17. Lieu TA, Fleisher GR. Schwartz JS: Cost-effectiveness of rapid latex agglutination testing and throat culture for streptococcal pharyngitis. Pediatrics 1990;85246-256.
Reprint no. 47/1/63042 Address for reprints: Steven M Green, MD, FACEP Lama Linda University Medical Center Emergency Medicine Residency Program A-1 08 11234 Anderson Street Lama linda, California 92354 909-824-4085 Fax 909-478-4121
REFERENCES 1. Kline JA. Runge JW: Streptococcal pharyngitis: A review of pathophysiology, diagnosis, and management. J Emerg Med1994;12:665-680. 2. Dajani AS, Bisno AL, Chung KJ, et al: Prevention of rheumatic fever. Circulation 1988;78:1 0821086. 3. Taylor RB, Werman HA, Rund DA: Journal club: Streptococcal pharyngitis: Emerging concepts. Am J Emerg Med1988;6:306-311. 4. Kellogg JA, Manzella JP: Detection of group Astreptococci in the laboratory or physician's office. JAMA 1986;255:2638-2642. 5. Tompkins RK, Burnes DC, Cable WE: An analysis of the cost- effectiveness of pharyngitis management and acute rheumatic fever prevention. Ann Intern Med 1977;86:481-492. 6. Vukmir RB: Adult and pediatric pharyngitis: A review. J Emerg Med 1992;1 0:607-616. 7. Wegner DL, Witte DL, Schrantz RD: Insensitivity of rapid antigen detection methods and single blood agar plate culture for diagnosing streptococcal pharyngitis. JAMA 1992;267:695-697. 8. Harbeck RJ, Teague J, Crossen GR, et al: Novel, rapid optical immunoassay technique for detection of group A streptococci from pharyngeal specimens: Comparison with standard culture methods. J Clin Microbiol1 993;31 :839-844. 9. Gerber MA, Randolph MF, Chanatry J, et al: Antigen detection test for streptococcal pharyngitis: Evaluation of sensitivity with respect to true infections. J Pediatr 1986;108:654-658.
406
ANNALS OF EMERGENCY MEDICINE
25:3
MARCH 1995