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. 2000 Jun 17;320(7250):1665.

Length of penicillin treatment of streptococcal infections

Is seven days of treatment as effective as 10 days?

Dan Michaeli 1
PMCID: PMC1127435  PMID: 10905829

Editor—Zwart et al recommend seven days of treatment for streptococcal infections as opposed to three days.1 For several decades we were educated to continue penicillin for such cases for no fewer than 10 days.2 The rationale was that streptococci must be eradicated to prevent rheumatic fever and that this was achievable only after 10 days of treatment. This was based on bacteriological, epidemiological, and clinical observations. The cost of oral penicillin is almost negligible, and I think we need more assurance to be persuaded to cut treatment to only seven days. Is there any study that will prove that treatment for seven days is as effective as treatment for 10 days for preventing rheumatic fever?

References

  • 1.Zwart S, Sachs APE, Ruijs GJHM, Gubbels JW, Hoes AW, de Melker RA. Penicillin for acute sore throat: randomised double blind trial of seven days versus three days treatment or placebo in adults. BMJ. 2000;320:150–154. doi: 10.1136/bmj.320.7228.150. . (15 January.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Christie AB. Streptococcal infections—scarlet fever. In: Christie AB, editor. Infectious diseases: epidemiology and clinical practice. Edinburgh: Livingstone; 1969. p. 983. [Google Scholar]
BMJ. 2000 Jun 17;320(7250):1665.

Antibiotics should not be used for self limiting illnesses

R Fleetcroft 1

Editor—I have two concerns about Zwart et al's article1-1: firstly, the methodology, and, secondly and more importantly, that it was conceived at all, in view of the issue of antibiotic use.

The study had an unusually high number of exclusions (36.7%), and 26.6% of the patients were not randomised. The secret code of treatment was broken at the request of the doctor or the patient. There was a faster resolution in the patients in the seven day treatment arm at two days than in the three day treatment arm at two days, despite identical treatment, and I am not convinced by the authors' explanation. A possibility concerning all the above points is that the randomisation was not successful, and therefore the results of the trial may not be secure.

However, these doubts are minor compared with the real issue, which is how we use the precious resource of antibiotics. Resistance to commonly used antibiotics is rising fast.1-2 The increasing use of antibiotics encourages resistant organisms in patients and in the community.1-3 In most cases antibiotics do not prevent complications.1-4,1-5 Finally, antibiotics have at best mild to modest benefit in pharyngitis.

If we continue to prescribe antibiotics for self limiting illnesses where there is small benefit at most, we will see an increase in the incidence of serious resistant infections such as pneumonia and meningitis, and in the mortality inevitably associated with these infections. Our resolution for the new millennium should be to stop prescribing antibiotics for minor self limiting conditions, to allow nature to heal these, and to save antibiotics for what they were designed for in the first place—serious and life threatening disease.

References

  • 1-1.Zwart S, Sachs APE, Ruijs GJHM, Gubbels JW, Hoes AW, de Melker RA. Penicillin for acute sore throat: randomised double blind trial of seven days versus three days treatment or placebo in adults. BMJ. 2000;320:150–154. doi: 10.1136/bmj.320.7228.150. . (15 January.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-2.Johnson AP, Speller DCE, George RC, Warner M, Domingue G, Efstratiou A. Prevalence of antibiotic resistance and serotypes in pneumococci in England and Wales: results of observational studies in 1990 and 1995. BMJ. 1996;312:1454–1456. doi: 10.1136/bmj.312.7044.1454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-3.Arason VA, Kristinsson KG, Sigurdsson JA, Stefansdottir G, Molstad S, Gudmundsson S. Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children? Cross sectional prevalence study. BMJ. 1996;313:387–391. doi: 10.1136/bmj.313.7054.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-4.Howie JGR, Foggo BA. Antibiotics, sore throats, and rheumatic fever. J R Coll Gen Pract. 1985;35:223–224. [PMC free article] [PubMed] [Google Scholar]
  • 1-5.Taylor JL, Howie JG. Antibiotics, sore throats and acute nephritis. J R Coll Gen Pract. 1983;33:783–786. [PMC free article] [PubMed] [Google Scholar]
BMJ. 2000 Jun 17;320(7250):1665.

The data do not support the conclusions

Erdem I Cantekin 1

Editor—Zwart et al conclude from a placebo controlled randomised clinical trial that seven days of penicillin treatment for symptoms of acute sore throat is better than three days of treatment.2-1 In the accompanying editorial, one of the authors of the Cochrane review on antibiotics for sore throats (8 hours' benefit) is puzzled by the anomalous trial data that are presented.2-2

As shown in figures 1 and 2 in Zwart et al's paper, the two primary outcome measures, resolution of symptoms and resolution of impaired daily activities, do not support those conclusions. The Kaplan-Meier plots show that at day 3 the resolution of symptoms in group 1 (seven days of penicillin) and group 2 (three days of penicillin) was significantly different, although both groups had received identical treatment. This unexplained twofold difference between the two penicillin groups carries over to misleading conclusions at day 7. Importantly, outcomes in group 2 were almost identical with those for group 3 (placebo) for the entire study period.

The following results emerge by simply reformulating the research question as: what is the benefit of an additional four days of penicillin treatment, after the initial three days? From figure 1, in the seven day and three day groups, patients who were free of symptoms from day 3 through to day 7 were 37% v15%; 50% v 25%; 70% v 43%; 80% v 55%; and 88% v 63% (thus differences in rates of cure are 22%, 25%, 27%, 25%, and 25%, respectively). As additional treatment in group 1 starts after day 3, when this point is taken as the baseline reference the relative benefits are 3%, 5%, 3%, and 3% for days 4 through 7. Similarly, the other primary outcome measure, resolution of impaired activity (figure 2), shows relative benefits of −2%, 3%, −1%, and 3%, indicating no cumulative benefits from the extra four days of penicillin.

The authors need to explain the anomalous cure rate advantages for patients in group 1 at the day 3 baseline. My prime suspect is the unaccounted differences in prognostic factors such as “sore throat days” at entry among the three treatment groups, perhaps inadvertently favouring the seven day group. Also, use of well defined disease duration (onset, entry, and resolution) in life table analyses may clarify these puzzling results.

Because the findings show equivalence of placebo to three days of penicillin in treating symptoms of acute sore throats, I see no reason for the Cochrane review of Del Mar and colleagues to be revised.2-3

References

  • 2-1.Zwart S, Sachs APE, Ruijs GJHM, Gubbels JW, Hoes AW, de Melker RA. Penicillin for acute sore throat: randomised double blind trial of seven days versus three days treatment or placebo in adults. BMJ. 2000;320:150–154. doi: 10.1136/bmj.320.7228.150. . (15 January.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2-2.Del Mar C. Sore throats and antibiotics. BMJ. 2000;320:130–131. doi: 10.1136/bmj.320.7228.130. . (15 January.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2-3.Del Mar C, Glasziou PP Cochrane Collaboration, editors. Cochrane Library. Issue 3. Oxford: Update Software; 1996. Do antibiotics shorten the illness of sore throat? [Google Scholar]
BMJ. 2000 Jun 17;320(7250):1665.

Life tables should be used with caution

Peter Burke 1

Editor—Both Fleetcroft and Cantekin point out a curious anomaly in life table analysis of recovery from acute illness. If the outcome measure chosen is the day on which symptoms last occurred rather than the end of the period of continuous symptoms, the kind of pattern observed in Zwart et al's study is almost unavoidable.3-1

Imagine two patients—Bob in the seven day group and Paul in the three day group. Both get better after 24 hours, but Paul relapses on day 5 and recovers on day 7. On the life table Bob seems to have recovered in the crucial first three days whereas Paul does not. Hence the early takeoff of the recovery curve in the seven day group. It does not in any way indicate allocation bias between the groups.

Perhaps the lesson is that life tables should be used with caution for data of this kind.

References

  • 3-1.Zwart S, Sachs APE, Ruijs GJHM, Gubbels JW, Hoes AW, de Melker RA. Penicillin for acute sore throat: randomised double blind trial of seven days versus three days treatment or placebo in adults. BMJ. 2000;320:150–154. doi: 10.1136/bmj.320.7228.150. . (15 January.) [DOI] [PMC free article] [PubMed] [Google Scholar]
BMJ. 2000 Jun 17;320(7250):1665.

Care must be taken when extrapolating data

Paul Little 1,2,3,4, Ian Williamson 1,2,3,4, Greg Warner 1,2,3,4, Michael Moore 1,2,3,4

Editor—The high prevalence of Centor criteria, fever, and quinsy (1:60 untreated) in Zwart et al's patients4-1 compared with patients from an unselective trial (1:400) or routine data4-2,4-3 confirms that pre-trial selection probably occurred, but details of pre-selection are a little unclear.

The severity of symptoms is not presented. Analgesic use was similar in the trial groups until day 4. Symptom relief after this—when symptoms are milder—may not be clinically important. This is supported by the lack of difference in time off school and work. The estimated 1-2 days' benefit must also be put in the context of the much larger data set from the systematic review—suggesting a benefit of 8 hours to half a day.4-4

Perhaps the most important finding is that quinsy may be prevented. The Cochrane review4-4 relies heavily (76% of the weight) on a study of hospitalised patients given parenteral penicillin, where quinsy was common (1:18)—that is, not generalisable. The Centor criteria are crude because they were validated against the throat swab.

Nevertheless, the current trial supports the finding of another trial4-5 that crude antibiotic targeting to a clinical subgroup may prevent quinsy. However, since most patients were unwell with fever, targeting clinical subgroups may be no better than the general practitioner's overall judgment that the patients are not unwell systemically: these patients are at low risk irrespective of clinical signs—20% of the 716 patients had three out of four Centor criteria, and the only patient who developed quinsy did not fulfil the Centor criteria.4-2,4-3

Care must be taken in extrapolating efficacy trials to effectiveness in routine settings. Tablet counting and repeated examination may improve compliance, thus altering estimates of efficacy. With regard to symptoms, in an effectiveness trial (no repeated examination or tablet counting) patients with a very similar cluster to the Centor criteria, but who were well systemically, showed a benefit from antibiotics of a fraction of a day.4-2 With regard to complications, the computerised notes for five years in two contrasting practices documented nine cases of quinsy after presentation to the doctor: six received penicillin—so, preventing 100% of quinsy after sore throat, as implied by the efficacy trial results of Zwart et al and Dagnelie et al,4-5 is perhaps unlikely in everyday practice.

The results of Zwart et al's study must be put in the context of the presenting population, other evidence, and the possible difficulties of generalising evidence from efficacy trials to effectiveness in routine settings.

References

  • 4-1.Zwart S, Sachs APE, Ruijs GJHM, Gubbels JW, Hoes AW, de Melker RA. Penicillin for acute sore throat: randomised double blind trial of seven days versus three days treatment or placebo in adults. BMJ. 2000;320:150–154. doi: 10.1136/bmj.320.7228.150. . (15 January.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4-2.Little PS, Williamson I, Warner G, Gould C, Gantley M, Kinmonth AL. An open randomised trial of prescribing strategies for sore throat. BMJ. 1997;314:722–727. doi: 10.1136/bmj.314.7082.722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4-3.Little PS, Gould C, Williamson I, Warner G, Gantley M, Kinmonth AL. Reattendance and complications in a randomised trial of prescribing strategies for sore throat: the medicalising effect of prescribing antibiotics. BMJ. 1997;315:350–352. doi: 10.1136/bmj.315.7104.350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4-4.Del Mar C, Glaziou P Cochrane Collaboration, editors. Cochrane Library. Issue 3. Oxford: Update Software; 1998. Antibiotics for the symptoms and complications of sore throat. [Google Scholar]
  • 4-5.Dagnelie CF, Van der Graf Y, De Melker R, Touw-Otten FWMM. Do patients with sore throat benefit from penicillin? A randomised double blind placebo controlled clinical trial with penicillin V in general practice. Br J Gen Pract. 1996;46:589–593. [PMC free article] [PubMed] [Google Scholar]
BMJ. 2000 Jun 17;320(7250):1665.

Authors' reply

Sjoerd Zwart 1,2,3, Alfred Sachs 1,2,3, Arno Hoes 1,2,3, Ruut de Melker 1,2,3, Gijs Ruijs 1,2,3, Jan Gubbels 1,2,3

Editor—Michaeli comments on the risk of rheumatic fever when prescribing penicillin for fewer than 10 days. Indeed, in areas with poorer living conditions than in the Netherlands, a 10 day course of penicillin is needed. The distribution of the T/M subtypes of group A streptococci among our patients and among healthy controls will be published shortly. Rheumatogenic subtypes were cultured in patients as well as in controls.5-1

We were surprised by the difficulties experienced by Fleetcroft, Cantekin, and also by Del Mar in his editorial,5-2 concerning the methodological question of how to present the resolution of symptoms when they recurred during the first week of observation. A survival analysis gave us the most realistic picture of any difference in duration of symptoms between the treatment groups. Unfortunately, the results from the three day penicillin group (with 40% recurrences in the first week) had to be forced into the Kaplan-Meier straitjacket by using the definition of permanent resolution of symptoms. We do not agree with Cantekin's interpretation of our findings as we chose the endpoint of permanent resolution of symptoms. Burke's comments support our earlier explanation.

Little and colleagues focus on the generalisability of the results, which is the most relevant issue of any clinical trial. Indeed, the 21% of patients who did not meet the required number of clinical criteria was lower than the 50-60% rate we expected from the results of a previous study in the Netherlands.5-3 Probably the participating general practitioners underreported the number of patients with sore throats who were not eligible “at first sight.”

We agree with Little et al that we studied a selected population. However, this was our intention. We tried to mimic the general practitioner's daily practice of patient selection. In this way, we were not surprised to find that penicillin was more effective than in Little et al's population, which probably included many patients with a viral infection.5-4 Interestingly, Little et al's open trial also included a subgroup of 94 ill patients with a symptom-sign complex similar to our complete patient group. Their table 3 indicates that antibiotics reduced the duration of sore throat in these patients.

Unlike Little et al, we are not worried that the artificial use of throat swabs and medication tray biased the recording of symptoms in the diary. How can this bias play a role if randomised patient groups are compared? Our trial was not designed to study whether penicillin would prevent quinsy or peritonsillar cellulitis. Nevertheless, the reason that the protective effect of penicillin in our patient group seemed to be at the same level as in some studies in the 1950s may again be explained by the strict inclusion criteria we used, selecting probably the most ill patients, most of them having a throat swab that was positive for streptococci.

We agree with Little et al that the population studied should be taken into account when the findings are generalised. However, because we found important and relevant effects of penicillin, we feel free to reverse the association between result and population. To incite further discussion on the management of sore throat in adults we therefore recommend for other routine settings, such as the primary care setting in the United Kingdom, the selection criteria that we used in our study and that are also used in Dutch daily practice.

Fleetcroft and Little et al fear that penicillin will be used as a routine drug in a routine setting, thus leading to medicalised patients and resistant strains. We share their fear, but believe that doctors and patients can make a well balanced decision only when they are informed not only about the costs and adverse effects of antimicrobial treatment, but also about the benefits.5-5

References

  • 5-1.Zwart S, Ruijs GJHM, Sachs APE, van Leeuwen WJ, Gubbels JW, de Melker RA. Beta-hemolytic streptococci isolated from acute sore throat patients: cause or coincidence? A case-control study in general practice. Scand J Infect Dis 2000 (in press). [DOI] [PubMed]
  • 5-2.Del Mar C. Sore throats and antibiotics. BMJ. 2000;320:130–131. doi: 10.1136/bmj.320.7228.130. . (15 January.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5-3.Dagnelie CF, Touw-Otten FWMM, Kuyvenhoven MM, Rozenberg-Arska M, de Melker RA. Bacterial flora in patients presenting with sore throat in Dutch general practice. Fam Pract. 1993;10:371–377. doi: 10.1093/fampra/10.4.371. [DOI] [PubMed] [Google Scholar]
  • 5-4.Little PS, Gould C, Williamson I, Warner G, Gantley M, Kinmonth AL. An open randomised trial of prescribing strategies for sore throat. BMJ. 1997;314:722–727. doi: 10.1136/bmj.314.7082.722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5-5.Graham A, Fahey T. Sore throat: diagnostic and therapeutic dilemmas. BMJ. 1999;319:173–174. doi: 10.1136/bmj.319.7203.173. [DOI] [PMC free article] [PubMed] [Google Scholar]

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