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Review Article

Hostage to History

The Duration of Antimicrobial Treatment for Acute Streptococcal Pharyngitis

Radetsky, Michael MD, CM

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The Pediatric Infectious Disease Journal: May 2017 - Volume 36 - Issue 5 - p 507-512
doi: 10.1097/INF.0000000000001480
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Abstract

Decisions regarding duration of antimicrobial therapy occupy a central place in the practice of infectious disease. Yet, critical evaluations of duration of therapy have been carried out in very few infectious diseases,1 and “for most infections, there is limited evidence available to support a specific duration of treatment.”2 Instead, the duration of therapy is often based on anecdotal data, clinical intuition, habit or “expert opinion.”3 Default lengths of therapy are commonly used for the treatment of the most common infections. A perusal in general medical textbooks of treatment recommendations for common infections (eg, pneumonia, urinary tract infections, acute otitis media, cellulitis, sinusitis, bacterial adenitis) shows that 7-, 10- and 14-day antimicrobial regimens predominate.4–8 These duration defaults are also found in recommendations for the treatment of more serious infections, such as bacterial meningitis.9

For the past 60 years, 10 days of oral antibiotic therapy has been the standard duration of treatment for acute streptococcal pharyngitis.10 Recently, the scientific rationale for this duration standard has been questioned, both in the medical and the lay press.11,12 Nevertheless, a 10-day treatment course continues to receive faithful reaffirmation. Because the 10-day rule was not originally derived from scientific data, its tenacity can only be explained by knowledge of its historical evolution.

DURATION STRATEGIES DURING THE EARLY YEARS OF ANTIMICROBIAL THERAPY

Following widespread experience with sulfonamides and penicillin during the Second World War, the general approach to treatment duration was summarized by Dr. Chester Keefer,13 the “penicillin czar” for civilian use of the new antibiotic during the 1940s: “It is impossible to give any specific rules concerning dosage and duration of treatment…The only rule to follow is to treat the individual patient and study the response to treatment.” Ample, even extended, antimicrobial therapy was encouraged by no less a luminary than Alexander Fleming14: “The duration of a course of systemic penicillin will depend upon the nature of the infection. It is far better to continue the administration for a few days too long than to cut the course short and risk a relapse.”

This was an era of antimicrobial therapy in which the duration of treatment was imprecisely formulated but usually tethered to clinical markers of improvement: “Until the patient seemed entirely well clinically…The dose was never reduced before the temperature had been normal for 1 week.”15 “For 2 weeks after the temperature has dropped to normal…and the patient appears well.”16 “The disease is well controlled when the patient shows a decided improvement in the mental state, has been essentially afebrile for 24–48 hours and has received a total of 15–20 g of the drug.”17 There seemed little enthusiasm for more precise treatment schedules. After all, largely fatal infections were miraculously responding to drug treatment for the first time. Grateful physicians simply followed their clinical instincts. As Harry Dowling, one of the early pioneers of infectious disease medicine, observed: “The duration of treatment just evolved. There was no rationale for any single length of time. We saw how long it took for the temperature to come down and gave antibiotics until it did, and then some. Duration was unimportant in light of what came before. If we treated a few extra days, who cared? We always wanted to be sure.”9

Yet, even at this early stage, there appeared a desire to standardize treatment duration. For example, the guidelines published by Dingle and Finland18 in 1942 recommended that meningococcal meningitis be treated for 2–5 days, pneumococcal and streptococcal meningitis for 7–14 days and staphylococcal and Hemophilus meningitis for 2–3 weeks. The predilection for treatment recommendations to be expressed as multiples of weeks had already emerged.

CLINICAL TRIALS OF ANTIMICROBIAL PREVENTION OF ACUTE RHEUMATIC FEVER

Before the early 1950s, throat cultures were rarely obtained unless diphtheria was suspected.19 Although streptococcal pharyngitis had been described since the 1920s,20 it generated little concern in practice, except in the context of scarlet fever, an infection long feared by all clinicians.21 The Red Book published by the American Academy of Pediatrics did not even mention treatment for streptococcal pharyngitis in its 1951 edition.22 The general availability of antimicrobials was soon to change that.

In 1939, sulfanilamide was shown to be effective in preventing streptococcal respiratory infections and relapses in rheumatic fever.23 By 1945, it was known that sulfonamides could terminate outbreaks of scarlet fever by eradicating streptococcal carriage.24 In the same year, it was shown that penicillin, finally released for civilian use, could successfully treat acute streptococcal pharyngitis and tonsillitis.25 The first, large controlled trial of antimicrobials for group A streptococcal infection was published in 1946 under the auspices of the Commission on Hemolytic Streptococcal Infections, a part of the Board for the Investigation of Epidemic Diseases of the US army.26 There was no predetermined duration of therapy. Most patients received between 1 and 5 days of antimicrobials. Symptomatic improvement was seen in the penicillin group. Neither drug prevented acute rheumatic fever, which occurred in 3% of the army recruits.

Then, in 1947, a study of streptococcal pharyngitis was conducted at the House of the Good Samaritan.27 This was a Boston charitable hospital founded in 1860 by Anne Smith Robbins to care for chronically ill women and children who could not be helped in existing hospitals.28 Over time, the House of the Good Samaritan came to specialize in the treatment of rheumatic fever under the guidance of T. Duckett Jones.29 In order to prevent the spread of group A streptococcus in this closed, high risk hospital, any patient with acute streptococcal pharyngitis or chronic streptococcal carriage was treated with a murderous regimen of 10,000 units of penicillin intramuscularly every 2 hours for 10 days. This strategy achieved pharyngeal eradication in 17 of 20 patients. This appears to be the first published study to use a 10-day treatment course for any infectious disease. No explanation was given as to why a 10-day course was chosen.

The next year, a second study from the House of the Good Samaritan was published in order to determine if similar eradication rates could be achieved through the dosing of oral penicillin.30 A custom formulation of buffered penicillin G tablets was used. As with the prior study, treatment was continued for 10 days. Although 94% of patients had prolonged eradication of group A streptococcus in the intramuscular study, only 78% achieved similar results with oral penicillin. Even though no comparison was made with either shorter or longer treatment courses, the investigators were able to conclude: “Penicillin therapy of streptococcic infection should be continued for a sufficiently long period of time in order to prevent a flare-up of the infection, but in our experience a sufficiently long period would seem to be closer to 10 days than to 5 days.”30 A third study from the same institution, which compared intramuscular with oral penicillin G, also used a 10-day treatment course, again without explanation.31

Beginning in 1950, the results of the extensive clinical trials to prevent epidemic acute rheumatic fever at Francis E. Warren Air Force Base in southeastern Wyoming were published by Wannamaker, Rammelkamp, Denny and colleagues.32,33 Depot preparations of procaine penicillin suspended in oil were given intramuscularly either as a single dose on the day of diagnosis or as multiple doses spread out over 4 days. Oral antimicrobials were not used. The 3% risk of subsequent acute rheumatic fever seen in controls was reduced to 1% or less with use of injectable depot penicillin. In 2 further studies, the Warren Air Force Base investigators compared intramuscular treatment of depot penicillin with oral chlortetracycline or oxytetracycline.34,35 While the depot penicillin was given in multiple doses over 4 days, the chlortetracycline and oxytetracycline were given for either 4 or 5 days. There were no data presented regarding the ability of the oral antimicrobials to prevent acute rheumatic fever. Depot penicillin was superior in the eradication of streptococcal carriage.

Because of the epidemic nature of group A streptococcal infection at Warren Air Force Base, a program of base-wide prophylaxis was undertaken in 1951.36 All recruits were assigned to 1 of the 3 treatment arms: oral penicillin G 1 million units twice daily for 5 days, oral penicillin G 1 million units twice daily for 10 days or the control group. Although over 1000 healthy subjects were enrolled for each treatment group, streptococcal carriage rates were calculated on only 150 men in each treatment group. The clinical resolution of acute streptococcal infection was not investigated. The prevention of acute rheumatic fever was not investigated. Fifteen days after therapy, the control group had approximately a 25% carriage rate, the 5-day group 15% and the 10-day group 10%. No statistical analysis was performed, and no explanation was given for the choices of duration. Nevertheless, the investigators concluded: “These studies indicate that it is probably necessary for penicillin to be given for approximately 10 days to eliminate group A streptococci from the throats of carriers.”36

In the same year, Breese37 published the first private office-based investigation of treatment of streptococcal pharyngitis. Depot penicillin, oral potassium penicillin, chlortetracycline and sulfonamides were all used and reported. The depot penicillin was given every 3 days in 2 or 3 doses, while the oral antimicrobials were each given for anywhere from 5 to 12 days. In 1204 children treated with any medication on any schedule for community-acquired streptococcal tonsillitis or pharyngitis, only 1 case of subsequent acute rheumatic fever occurred.

STANDARDIZATION OF TREATMENT DURATION

These published studies comprised the entire existing scientific literature when, in 1953, the Committee on Prevention of Rheumatic Fever of the American Heart Association Council on Rheumatic Fever and Congenital Heart Disease met to formulate the first guidelines for the prevention of acute rheumatic fever. The Committee consisted of Burtis Breese, Chairman, Drs. Rammelkamp and Massell from the Warren Air Force Base study group and 4 other physicians. Their recommendations were published that year.38 Both injectable depot procaine penicillin given every third day for 3 doses and oral penicillin given in divided doses for 10 days were recommended. By way of explanation, the Committee stated the following: “Penicillin is the drug of choice for treating streptococcic infections. Both the oral and the intramuscular routes of administration have been utilized successfully for penicillin therapy of streptococcic infections. Intramuscular injections have been proved to prevent rheumatic fever. The data on the value or oral penicillin as a preventative are less complete.”38 This was something of an overstatement because no study had ever been conducted to assess the ability of oral penicillin therapy to prevent poststreptococcal acute rheumatic fever. The Committee went on to say: “To be effective, therapy should be continued for the entire 10 days even though the temperature may return to normal and the patient may feel better within 1 or 2 days.”38 No literature citations or further justification accompanied these recommendations.

In 1955, a revision of these guidelines was published by the Committee on Prevention of Rheumatic Fever and Bacterial Endocarditis because “this revision has become necessary as knowledge concerning effective technics of control of streptococcal infections is increasing.”39 The Committee Chairman was T. Duckett Jones, who died 2 months before the publication of the guidelines. Four of the original Committee members remained, including Drs. Breese and Rammelkamp. After reaffirming the previous recommendations, the Committee stated: “When streptococcal infection is suspected, treatment should be started immediately. Penicillin is the drug of choice. Effective blood levels should be maintained for a period of 10 days [their italics] to prevent rheumatic fever by eradicating the streptococci from the throat. Penicillin may be administered by either intramuscular or oral route.”39 Once again, no justification was offered for the recommendation.

FURTHER INVESTIGATIONS AND FINAL CONSOLIDATION OF THE 10-DAY RULE

In the mid-1950s, a number of additional studies concerning the treatment of streptococcal disease were published. Of those, 4 studies deserve mention. Mohler et al40 demonstrated for the first time that compliance with oral penicillin treatment at home was poor in one-third of patients. The same group showed that eradication rates improved with the duration of oral therapy up to 7 total days but never reached that provided by a single injection of benzathine penicillin.41 Breese,42 and his Elmwood Pediatrics office colleague Frank Disney, showed that oral penicillin V taken for 10 days successfully treated 75% of cases of group A streptococcal infections. Finally, Breese and Disney43 compared single-dose intramuscular benzathine penicillin with 4 different treatment schedules of oral benzathine penicillin given over 8–10 days in the treatment of childhood streptococcal infections. Eradication rates varied from 61% to 81%, but unfortunately, no statistical analysis was performed. The next year, however, Breese and Disney44 published a second study, which corrected this defect. They demonstrated the superiority of 1 dose of injectable benzathine penicillin in eradicating throat streptococci when compared with 4 oral penicillin formulations, each given for 10 days. The difference was statistically significant.

In 1958, Catanzaro et al45 published the results of their retrospective reexamination of the Warren Air Force Base clinical trial data gathered during the epidemic streptococcal era of 1949–1954. The 5198 study patients represented 2 groups. Group I consisted of 3981 recruits who were treated for either exudative streptococcal pharyngitis/tonsillitis or scarlet fever. Of these, 2219 were given intramuscular depot penicillin, while 1762 had received an oral antimicrobial, either chlortetracycline, oxytetracycline or sulfadiazine. Group II were 1217 recruits who were thought to be asymptomatic streptococcal carriers and received either intramuscular or an oral antimicrobial for variable durations. All patients were included in the analysis. There were 49 (0.9%) cases of acute rheumatic fever among these 5198 patients that could be directly attributed to the preceding streptococcal infection. Unfortunately, follow-up cultures were only performed on 85% of group I patients and 50% of group II patients. To compensate for this failure, “[t]he patients whose bacteriologic results in the convalescent period were not available were assigned to the appropriate divisions with due adjustment for seasonal and technical variations and for drug and dosage schedules.”45 The exact mechanisms for this assignment and adjustment were not clearly described. Despite these considerable methodological difficulties, attack rates for acute rheumatic fever were calculated and compared with the “adjusted” results of actual and predicted follow-up cultures. About 2.8% of the category “original type isolated” developed acute rheumatic fever, compared with 1.4% of “different type isolated” and 0.3% of “group A organisms not isolated.” No statistical analysis was reported. The conclusion of the authors was declarative: “The data clearly indicate that when the infecting organism is not eliminated from the patient by therapy, the attack rate of rheumatic fever is not reduced appreciably.”45 With regards to oral therapy, the authors also declared (without explanation or literature citations): “Oral treatment must be maintained for at least 8 to 10 days if the convalescent-carrier rate is to be reduced appreciably.”45

Only the Warren Air Force Base trials contained sufficient data to assess the efficacy of acute rheumatic fever prevention—the original motive for the use of penicillin. Although subsequent studies investigated oral antimicrobial therapy of endemic streptococcal infections, primarily among children in community settings with low acute rheumatic fever rates, the clinical trials at Warren Air Force Base had been conducted on military recruits who were treated with injectable depot penicillin for exudative streptococcal pharyngitis/tonsillitis or scarlet fever under epidemic disease conditions. Despite these significant differences, the conclusions of the Catanzaro study were generalized to include acute streptococcal pharyngitis seen in all settings and in all populations. This study remains the primary justification for the assumption that pharyngeal eradication of group A streptococcus is a reliable surrogate marker for the prevention of acute rheumatic fever.

THE SPREAD OF THE 10-DAY RULE

By the late 1950s, 10-day therapy for streptococcal pharyngitis had become firmly established. Interestingly, with the exception of streptococcal pharyngitis, large clinical trials of antimicrobial therapy for other common infections were sparse. In this inchoate therapeutic world, the 10-day treatment duration for streptococcal pharyngitis, justified as it was by impressive clinical trials, became an attractive benchmark of duration for treatment of other infections. This gravitational pull toward a 10-day duration for antimicrobial therapy can be seen in a survey of antimicrobial treatment recommendations for various common infections that appeared in sequential editions of Nelson’s Textbook of Pediatrics and the Harrison’s Principles of Internal Medicine (and their immediate predecessors) from the years 1942 to 1979, in which 10 days vies with 7-day multiples for duration (Table 1). Even in 2016, the 20th edition of Nelson’s Textbook of Pediatrics recommends a general duration of 10 days of antimicrobial therapy for acute bacterial adenitis, cellulitis, acute otitis media, streptococcal pharyngitis, sinusitis and pneumonia. The 10-day rule for antibiotics also has become a fixture in the public consciousness, although not without some wonder: “Why do doctors prescribe antibiotics for 10 days?”46

TABLE 1
TABLE 1:
Duration of Antimicrobial Therapy for Common Infections

TREATMENT DURATION IN THE MODERN ERA

Since these original investigations into the prevention of acute rheumatic fever over 60 years ago, 3 dynamic changes in the United States have taken place: the falling incidence of acute rheumatic fever, the rising rate of penicillin failures and the use of nonpenicillin antimicrobials as therapy for streptococcal pharyngitis.

It has remained an unproven assumption that the results of the Warren Air Force Base studies—conducted on military recruits with highly symptomatic exudative pharyngitis/tonsillitis or scarlet fever—were applicable to a civilian population, in which the majority of cases of streptococcal infections were endemic, of mixed severity and occurred primarily in children.47 During the epidemic group A streptococcal infection in the military, the rate of acute rheumatic fever in untreated young adults was a substantial 3%.45 In civilian populations, however, the risk of acute rheumatic fever after untreated streptococcal sore throat has been much lower. The large civilian studies of children conducted in Chicago reported a rate of only 0.4% even in untreated children and, therefore, could not validate the results of the military prevention studies.48 Similarly, a more recent study of oral penicillin treatment of streptococcal pharyngitis in indigenous Maori or Pacific Island children could not confirm the benefit of primary penicillin prophylaxis.49 By the 1980s, the rate of acute rheumatic fever in the United States was 0.64 cases per 100,000 in the general population.50 Occasionally, there would be localized outbreaks of acute rheumatic fever. These were attributed to the transient appearance of rheumatogenic strains of group A streptococcus.51 In general, however, the risk of acute rheumatic fever has remained low.

Streptococcal failure rates have increased over time despite continued susceptibility to penicillin. At Elmwood Pediatrics in Rochester, NY—the pediatric practice founded by Burtis Breese—failure rates after oral antibiotic therapy for streptococcal pharyngitis rose from 9% in 1975–1979 to 25.9% in 1980–1984.52 By the year 2000, up to 35% of patients treated with oral penicillin V and 37% of those treated with injectable benzathine penicillin G were microbiological treatment failures.53 These rising failure rates, combined with the continued low risk of acute rheumatic fever, obviously posed conceptual problems for those who would equate success in streptococcal eradication with success in acute rheumatic fever prevention.

The first large study of short-course penicillin treatment was published in 1981 by Schwartz et al.54 A total of 191 children aged 1–18 years with clinical findings suggestive of group A streptococcal infection and a positive streptococcal throat culture were enrolled. Patients were randomized to receive 7 or 10 days of penicillin. Follow-up throat cultures were obtained at 4–6, 10–12, 20–22 and 27–30 days. Compliance monitoring was accomplished with penicillin detection in urine on days 4–7. Penicillin failures were defined as the recovery of the same strain of organism on any follow-up culture. Overall, the 7-day group had a 31% failure rate, while the 10-day group had an 18% failure rate (P = 0.05). Interestingly, the failures within the 7-day group were retreated with 10 days of penicillin V, and 30% of those failed again. There was no correlation between compliance and eradication. A similar study was published by Gerber et al55 in 1987, in which 5- and 10-day durations of oral penicillin V were compared. A total of 172 patients were enrolled. The failure rate in the 5-day group was 18%, while that in the 10-day group was 6% (P < 0.05). If pharyngeal eradication was the goal of therapy, then it became apparent that short-course therapy with oral penicillin was undesirable.

However, nonpenicillin oral antimicrobials have been investigated as alternatives for the treatment of streptococcal pharyngitis. Since 1990s,56 a series of eradication studies have been published using alternative antimicrobials given for <10 days. These have been analyzed in a number of meta-analyses.57,58 The most recent was published by the Cochrane Database of Systematic Reviews in 2012.59 In all, 20 studies with 13,102 childhood cases of acute group A streptococcal pharyngitis were included in the analysis. Although the majority of studies were at high risk of bias, they nevertheless contained consistent results. This systematic review found that 3–6 days of oral nonpenicillin antimicrobials (primarily cephalosporins) achieved an equivalent streptococcal eradication rate to 10 days of oral penicillin. This result was in agreement with previous meta-analyses. No conclusion could be drawn regarding the efficacy of acute rheumatic fever prevention.

DISCUSSION

This history shows that the emergence of 10 days of oral penicillin as standard for the prevention of acute rheumatic fever was not originally derived from scientific data. It just “evolved.” The 10-day benchmark that has become standard for the treatment of streptococcal pharyngitis has influenced the recommended treatment duration for many other common infections—many of which have settled on a 10-day treatment course as well. This 10-day therapy has never received scientific verification. Rather, long and settled usage appears to have sanctified the practice. Augmenting the influence of historical pedigree is the visceral contentment that the number 10 provides and that other contiguous numbers do not enjoy.60 The number 10 has occupied a preferred place in human affairs ever since the ancient Egyptians adopted a base-10 numbering system.61 The number 10 has had potent links with religious and mystic belief systems throughout human history.62 The fact that we are a decimal society makes our fondness for the number 10 reasonable. Adjacent integers lack this inherent power. For example, despite substantial advantages, all attempts to introduce base 12 and alternative base mathematics into general usage have quickly foundered,63 and antimicrobial therapy for 12 days, much less 13, 11, 9 or 8 days, have never become common treatment options.

For these reasons, this 10-day rule has become axiomatic, “the standard against which other proposed treatments must be measured.”64 Not surprisingly, “it will be very difficult to alter prescribing practices of physicians to shorten therapeutic courses without a strong basis in evidence supporting the safety and efficacy of such changes.”65 Based on negative responses to a proposed change to short-course therapy with a nonpenicillin antimicrobial, the “strong basis” required to change behavior may need to be considerable. Hesitant practitioners reject the legacy of the 1958 Catanzaro study that eradication of pharyngeal colonization is equivalent to rheumatic fever prevention, and they observe that there is no proof that short-course therapy with a nonpenicillin antimicrobial can prevent acute rheumatic fever: “I think we need more assurance to be persuaded to cut treatment…Is there any study that will prove [my italics] that treatment for 7 days is as effective as treatment for 10 days for preventing rheumatic fever?”66 These critics point out that 10 days of oral penicillin is settled therapy with a long record of success and that there is no obvious benefit to a change in approach.67 Still others claim to have identified pervasive methodological errors in the studies of short-course therapy and express the fear that the use of more broad-spectrum antimicrobials to treat streptococcal pharyngitis might increase resistance rates in human pathogens and escalate the cost of therapy: after all, “change is one thing, progress is another.”68 For these reasons, the Red Book published by the Committee on Infectious Disease of the American Academy of Pediatrics continues to recommend 10 days of either penicillin V or amoxicillin as primary therapy for streptococcal pharyngitis.69

As most of the research on primary prevention of acute rheumatic fever occurred in the 1950s70 and no subsequent countervailing studies have been conducted, efforts to overcome physician resistance would require new, definitive, randomized, noninferiority therapeutic trials, in which short-course oral therapy for streptococcal pharyngitis with nonpenicillin antimicrobials would be compared with “standard” 10-day therapy with oral penicillin. Such trials would be impractical in areas of rare acute rheumatic fever because the numbers of subjects required to establish noninferiority would be prohibitive.71 Even in areas with a higher risk of acute rheumatic fever, the numbers of subjects that would be needed in each treatment group would be daunting. There appears to be little enthusiasm for the considerable organizational effort required to perform such trials. This is in contrast to the many studies now being conducted to define the minimal safe duration of antimicrobials for other more serious infections.72 The motivation behind these hospital-based studies is a composite desire to decrease the risk of antimicrobial-associated complications, to check the spread of resistant organisms by reducing institutional antimicrobial pressure and to control treatment costs by shortening hospital stay. None of these motivating factors pertains in the area of streptococcal pharyngitis. Hence, it is doubtful that therapeutic trials will ever take place to settle the issue of short-course therapy. Without such a “strong basis,” it is unlikely that mere criticism of historical precedents, however cogent, will overcome clinician resistance unless augmented by equally strong enabling recommendations for short-course therapy from expert consensus panels.

Ten days of penicillin therapy for acute streptococcal pharyngitis has the longest lineage of any antimicrobial recommendation in clinical infectious disease. The original choice of 10-days duration—rather than 11-days or 9-days duration—was without an initial rationale, but once made, it has endured. The 10-day rule appears to be an example of a more general phenomenon in clinical medicine, the fierce inertia of established usage: “As soon as a new but still unproved method of treatment is adopted by even a minority of the medical profession, it becomes virtually impossible to conduct the controlled trial that alone can furnish truly reliable evaluation of its effectiveness and its hazards.”73

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Keywords:

antimicrobial therapy; streptococcal pharyngitis; medical history

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