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Length of penicillin treatment of streptococcal infections
- Dan Michaeli (15 January 2000)
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The problem with seven day treatment of group A streptococcus tonsillitis /pharyngitis
- Munir E Nassar (17 January 2000)
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Antibiotics for sore throats? inappropriate therapy in the new mellennium
- R Fleetcroft (19 January 2000)
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On the seventh day ye shall NOT rest
- Gary Zentner (20 January 2000)
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For sore throats, seven days of penicillin is not superior.
- Erdem I Cantekin (20 January 2000)
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Re: For sore throats, seven days of penicillin is not superior.
- Peter Burke (24 January 2000)
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Importance and generaliseability of trial data
- Paul Little (25 January 2000)
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Authors' response
- Sjoerd Zwart (22 February 2000)
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Dan Michaeli, Chairman , Board of Directors Clalit Health Services, Israel
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The author recommends a 7 days treatment for streptococcal infections as opposed to 3 days. For several decades we were educated to continue penicillin for such cases for a period of 10 days , and no less ! The rationale was that eradication of streptococci is necessary to prevent rheumatic fever and was achievable only after 10 days of treatment . This was apparently 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 7 days. Is there any study that will prove that 7 days are as effective as 10 for preventing rheumatic fever ? Ref: Christie A.B. Infectious Diseases: Epidemiology and Clinical Practice, E.& S. Livingstone editors ,1969 p.983. |
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Munir E Nassar, volunteer tutor URMC, rochester, N Y N/A
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Although the article makes a definitive argument for the seven day treatment of Group A streptococcus pharyngitis/tonillitis with penicillin v, The authors seem to ignore that such a course of treatment, though superior to a three day course, is inadequate for the prevention of the sequalae of Group A streptococcus rheumatogenic strains M type 1,3,5,6,14,18,19,27,28. it is uncertain from the laboratory data presented whether typing was carried out. The traditionally recommended teatment for group A streptococcus upper respiratory infections is for 10 days, which has been found out to prevent the subsequent onset of acute rheumatic fever(*). Munir E Nassar, M.D. (*)- Dajani A S, Taubert K, Ferrieri P, et al.: Treatment of streptococcal pharyngitis and prevention of rheumatic fever. Pediatrics 96:758, 1995 |
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R Fleetcroft, GP principal, trainer, tutor, clinical governance lead Hemsby Norfolk UK
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This article concerns me in 2 ways, firstly with the methodology, but secondly and more importantly that it was concieved at all, in view of the issue of antibiotic usage. The study had an unusually high number of exclusions (36,7%). Not all the patients were randomised (26.6%).The secret code of treatment was broken at the wish of the doctor or the patient. There was a faster resolution of the patients in the 7 day treatment arm at 2 days, as compared to the 3 day treatment arm at 2 days despite identical treatment,and I am not entirely sure of the explanation given by the authors.Another 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 to the real issue which is how we use this precious resouce of antibiotics handed to us by our predecessors. Resistance to commonly used antibiotics is rising fast(1).The increasing use of antibiotics encourages resistant organisms within individuals themselves, and within the community (2).In the majority of cases antibiotics do not prevent complications (3),(4).Finally, antibiotics have at best mild to modest benefit in pharangitis (5). If we continue to prescribe antibiotics for self limiting illnesses where there is small benefit at most, we will see an increase in incidence of seious resistant infections such as pneumonia and meningitis, and inevitably assosiated mortality. Our resolution for the new millennium should be to stop prescribing antibiotics for minor self limiting conditions, allow nature to heal these in her successful way, and save antibiotics for what they were designed for in the first place-- serious and life threatening disease. (1)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;312:1454-6 (2)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 prevalance study BMJ 1996;313:387-91 (3)Howie JGR, Foggo BA Antibiotics, sore throats, and rheumatic fever JRCGP 1985;35:223-4 (4)Taylor JL, Howie JG, antibiotics, sore throats and acute nephritis.JRCGP1983;33:783-6 (5)Clinical Evidence. BMJ publishing issue 2 dec 1999 page586 |
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Gary Zentner, Paediatrician Clalit Health Services, Beth Hakerem, Jerusalem, Israel
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The outcome measures in this study related to symptomatic relief of sore throat. However, the prevention of rheumatic fever is still the most important aim of Penicillin treatment in Streptococcal throat infections, and to that end a 10-day course of Penicillin remains the gold standard of treatment. While rheumatic fever is certainly not a major problem in the Western world, when it occurs it is often very subtle in its presentation, causes very serious morbidity, and is still by no means rare. I am concerned that reducing the duration of treatment to less than 10 days is flirting with fate, and may be courting disaster. It may have been appropriate for the Creator to desist from His labours on the seventh day, but I will certainly continue treating my patients for a full ten days. Ref: Pichichero ME. Group A beta-hemolytic streptococcal infections. Pediatr Rev 1998 Sep; 19(9): 291-302 |
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Erdem I Cantekin, Professor of Otolaryngology University of Pittsburgh School of Medicine
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Based on the findings from a randomized double blind clinical trial, Professor de Melker and colleagues conclude that seven days of penicillin therapy is superior to three days of penicillin in treating acute sore throat symptoms. [1] In the accompanying editorial, Professor Del Mar, who co-authored the Cochrane review on the lack of efficacy of antibiotics for sore throat (8 hours benefit), is gently puzzled by the anomalous de Melker data. [2] The primary outcome measure of the trial, resolution of symptoms or resolution of impaired daily activities (figures 1 and 2), in fact do not support those conclusions reached by the authors. A cursory inspection of the Kaplan-Meier plots shows that at day three, the resolution of symptoms among the group 1 (seven days penicillin) and group 2 (three days penicillin) subjects were significantly different (37% v. 15%), although both groups had received the identical three days of penicillin therapy. This unexplained two-fold difference between the two groups is, at best, an unaccounted statistical fluke, and it carries over, to the misleading conclusions at day seven. Another way of looking into this data problem is by simply reformulating the research question as “What is the benefit from an additional four days of penicillin therapy, after the initial three days of therapy?”. The data are clear and compelling. This is how it goes. Day 3 through 7, among the treatment groups 1 and 2, the proportion of patients who were symptom free are 37% v. 15%, 50% v. 25%, 70% v. 43%, 80% v. 55%, and 88% v. 63%. Those figures lead to the cure rate differences of 22%, 25%, 27%, 25%, and 25%, respectively. Using day 3 as the reference point (since additional therapy in group 1 starts after this point), the relative benefits as measured from the day 3 baseline are 3%, 5%, 3%, and 3%, respectively, for days 4 through 7. This clearly demonstrates that there are no cumulative effects from the additional four days of penicillin. Similarly, the other primary outcome measure, resolution of impaired activity (figure 2), shows relative benefits of -2%, 3%,-1%, and 3%, respectively, for days 4 through 7. Again seven days of penicillin has no additional effect over three days of penicillin for sore throats in resolving impaired activity. The authors, I think, have a scientific obligation to explain the anomalous cure rate advantages reported for group 1 patients at the 3 day baseline. My guess, among other things, is the unaccounted differences in prognostic factors at entry among the three treatment groups. For example, the onset of the sore throat is a very important prognostic factor. The larger the “sore throat days” at entry, the shorter would be the duration of symptoms. Table 1, the listing of baseline characteristics, indicates some advantage favoring group1 with respect to the “sore throat days”. If the authors reanalyze their data and calculate the proper disease duration (day of onset, day of entry, and day of resolution), and then correct the life-tables by accounting for prognostic factors, I am confident that their conclusions would change. If not, they at least would have an explanation for the two-fold difference observed at day three among the two identically treated patient groups. Since the present results show that the placebo group is doing as well as the three days of penicillin group in treating the symptoms of acute sore throats, I see no reason that the Cochrane review of Del Mar and colleagues should be remanded. [3] It is somewhat astounding that the peer review of BMJ did not detect this simple fallacy embodied in the data analysis before publication. This is a well designed and carefully conducted randomized clinical trial with health policy implications. It certainly deserves a better data analysis. References: 1. Zwart S, Sachs APE, Ruijs GJHM, et al. Penicillin for acute sore throats: randomised double blind trial of seven days versus three days of treatment or placebo in adults. BMJ 2000;320:150-154. 2. Del Mar C. Sore throats and antibiotics. BMJ 2000;320:130-131. 3. Del Mar C, Glasziou PP. Do antibiotics shorten the illness of sore throat? The Cochrane Library. Acute Respiratory Infections Module at the Cochrane Database of Systematic Reviews (updated 02 December 1996). Oxford: Update Software, 1997. Erdem I. Cantekin
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Peter Burke, Tutor in General Practice Oxford
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Both Dr Fleetwood and Prof Cantekin point up 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 the study of Zwart et al is almost unavoidable. Imagine 2 patients, Bob in the 7-day group, Paul in the 3 day group. Both get better after 24 hour but Paul, unsurprisingly, relapses on day 5 and recovers on day 7. On the life table Bob appears to have recovered within the crucial first 3 days while Paul does not. Hence the early take- off of the recovery curve in the 7-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. |
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Paul Little, MRC Clinician Scientist Southampton University
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Dear Editor, We congratulate Dr Zwart and colleagues for providing a very valuable addition to the literature[1], but would like to highlight several important issues raised by the trial. Regarding generaliseability, the authors state that 1147 patients contacted 55 GPs in two years, 21% did not fulfil the Centor criteria[2], and 79% of those with the criteria had a positive throat swab. This is, we are sure, unintentionally misleading, but it implies that the trial population are representative of those presenting to GPs. Inevitably in general practice trials some selection occurs, and this can be difficult to document, but unless the patients in Holland are very different, 1147 patients represents a fraction of those presenting to GPs [3], and no data is provided about potential selection bias compared to the larger presenting population. Assuming 1) those with the Centor criteria who were not randomised had a similar prevalence of positive throat swabs, and 2) none of those without the Centor criteria has a positive throat swab (both conservative assumptions), then the 1147 patients had a prevalence of positive throat swabs of at least 63% i.e. rather unrepresentative of UK patients. Similarly the high prevalence of fever, and of quinsy in untreated patients (1:60) - compared to relatively unselected patients in a UK trial (1:400) [4; 5] or routine data [6] - indicate this is a rather selected population. It would be helpful if the authors clarified information about the presenting population from which their patients were drawn, and if possible clarified the possible biases in pre-trial selection. Symptomatic benefit is a little difficult to assess from the trial results as the severity of symptoms is not presented. Analgesic use was similar in all trial groups until day four: symptom relief after four days when symptoms are milder may not be very important to patients. Similarly the lack of difference in time off school and work implies that the magnitude of activity restriction in the placebo group was modest. It would be very helpful if the authors provided information about severity, not just when activity/symptoms become normal. Even if there is significant benefit from severity of symptoms and activity restriction, the estimated figure of 1 and a half days of benefit must be put in context of the much larger data set from the systematic review of trials which estimates the likely duration of symptoms is of the order of a 8 [7]. Perhaps the most important outcome of the study is that quinsy may be prevented. This is important, since the systematic review of evidence to date indicates that antibiotics prevent quinsy [7], but relies heavily (76% of the weight) on a study where systemically unwell patients admitted to hospital were given parenteral penicillin, and where quinsy was common (1:18). This evidence cannot be safely extrapolated to healthier modern patients given oral antibiotics, mostly not systemically unwell, and with a much lower prevalence of quinsy. Although the Centor criteria are crude since they are validated against the throat swab [2] - which is neither sensitive nor specific compared to a rise in ASOT titres 8 - the authors [1] provide evidence supporting a similar recent trial [9] that antibiotic targeting (albeit crude) to a selected clinical subgroup of a modern population may prevent quinsy. However, since most patients were unwell with fever [1], targeting clinical subgroups may be no better than the GPs' overall judgement that the patient are not unwell systemically. In a recent trial this judgement identified the common group of patients who are at low risk of complications [4 5] irrespective of their clinical signs: 20% of the 716 patients [4 5] had 3 out of 4 Centor criteria, and the only patient who developed quinsy did not fulfil the Centor criteria. Although double blind randomised 'efficacy' trials provide the most important basis to make treatment decisions, care must still be taken extrapolating results to the effectiveness in routine settings. Patients who agree to efficacy trials may be unusual, and put themselves in the unusual psychological position of being unsure about treatment. Since both observational studies and trial evidence suggest that psychological variables probably determine clinical outcomes [10-12] this may plausibly modify effect size. A more specific issue about efficacy trials like Zwart et al1 is that unrealistic manipulation of patient behaviour may occur: patients had tablets counted, and repeated throat swabs and examinations. This doesn't happen routinely, and is likely to artificially improve compliance, altering estimates of efficacy. Regarding symptoms, in an effectiveness trial (no repeated throat swabs/examinations, no tablet counting) patients with a very similar cluster to the Centor Criteria, but not very unwell systemically, showed a benefit from antibiotics of a fraction of a day [4; 13] much less than reported in Zwart et al [1]. Regarding complications, the computerised notes for five years in two contrasting practices (deprived urban and market town) with 16000 patients documented 9 cases of quinsy/peritonsillar cellulitis following presentation to the GP with sore throat - i.e. approximately 1:400 - 1;800 [6], similar to the effectiveness trial [4]. 6 of these 9 patients had penicillin which did not prevent their quinsy from developing i.e. preventing 100% of quinsy following sore throat as implied by the efficacy trial results of Zwart et al [1] and Dagnelie et al[9] is perhaps unlikely in everyday practice.. We therefore very much welcome the results of this important study, but the results must be put in context of the population from which they are drawn, the other evidence available, and the possible difficulties of the generalising evidence from efficacy trials to effectiveness in routine settings. Yours Sincerely Dr Paul Little GP and MRC Clinician Scientist 1,2 Dr Ian Williamson1 GP and Senior Lecturer Dr Greg Warner2 GP Dr Michael Moore3 GP 1 Community Clinical Sciences, (Primary Medical Care Group), University of Southampton, Aldermoor Health Centre, Aldermoor Close, Southampton, England,SO15 6ST 2 Nightingale Surgery, Greatwell drive, Romsey, Hants SO51 7QN 3 Three Swans Surgery, Rollerstone street, Salisbury, Wilts SP1 1DX Reference List 1 Zwart S, Sachs A, Ruijs G, Hoes A, DeMelker R. Penicllin for acute sore throat: randomised double blind trial of seven days versus three days treatment or placebo in adults. B.M.J. 2000;320:150-154. 2 Centor RM, Witherspoon JM, Dalton HP. The diagnosis of strep throat in the emergency room. Med.Decis.Making 1981;1:239-246. 3 HMSO, OPCS. Morbidity statistics from general practice: Fourth National study 1991. HMSO, London:1994; 4 Little PS, Williamson I, Warner G, Gould C, Gantley M, Kinmonth AL. An open randomised trial of prescribing strategies for sore throat. B.M.J. 1997;314:722-727. 5 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. B.M.J. 1997;315:350-352. 6 Simo R, Avinash P, Belloso A, et al. Complications of sore throat are not rare. B.M.J. 1998;316 (21st February):631 7 Del Mar C, Glaziou P. Antibiotics for the symptoms and complications of sore throat. In: The Cochrane Data base of systematic reviews. The Cochrane Library 1998;last ammended 5/1998: 8 Valkenburg HA, Haverkorn MJ, Goslings WRO. Streptococcal pharyngitis in the general population. II. The attack rate of rheumatic fever and acute glomerulonephritis in patients not treated with penicillin. J.Inf.Dis. 1971;124:348-358. 9 Dagnelie CF, Van der Graf Y, De Melker R, Touw-Otten FWMM. Do patients with sore throat benefit from penecillin? A Randomised double blind placebo controlled clinical trial with penicillin V in general practice. B.J.G.P. 1996;46:589-593. 10 Olsson B, Tibblin G. Effect of patients' expectations on recovery from acute tonsilltis. Fam.Pract. 1989;6:188-192. 11 Little P, Gould C, Williamson I, Warner G, Gantley M, Kinmonth A. Clinical and Psychosocial predictors of illness duration from a randomised controlled trial of prescribing strategies for sore throat. B.M.J. 1999;319:736-737. 12 Stewart M. Effective physician-patient communication and health outcomes: a review. Can.Med.Assoc.J. 1995;152:1423-1433. 13 De Meyere M, Bogaert M, Verschraegen G, et al. Trial of prescribing strategies in sore throat. B.M.J. 1997;314:1904 |
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Sjoerd Zwart, general practitioner/ senior researcher Kampen/ Utrecht, The Netherlands
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We thank our colleagues Michaeli, Nassar and Zentner for their comment on the risk of rheumatic fever when prescribing penicillin for a period shorter than 10 days. Indeed , in areas with poorer living conditions than in The Netherlands, a 10-day course of penicillin is needed. Most of the rheumatogenic subtypes Dr Nassar mentioned were isolated from some of our group A streptococci-positive patients. The distribution of the T/M types among our patients and among healthy controls will be published shortly.[1] We were surprised by the difficulties experienced by Fleetcroft, by Cantekin, and also by Del Mar in his editorial comment,[2] in view of the methodological question 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 of symptom duration between the treatment groups. Unfortunately, the results of the 3-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 definitely do not agree with Cantekins interpretation of our findings. Apparently he did not understand that we chose the endpoint of permanent resolution of symptoms. We thank Dr Burke for his additional comments supporting our earlier explanation. Little and colleagues focus on the generalisability, being the most relevant issue of any clinical trial.[3] Indeed the 21% proportion of patients who did not meet the required number of clinical criteria was lower than the 50-60% rate we expected by interpreting the results of a previous study in The Netherlands.[4] Probably the participating GPs underreported the sore throat patients who were not eligible 'at first sight'. Naturally, the prevalence of positive throat swabs would have been much lower in this group. We agree with Little et al that we studied a selected population. However, this was exactly our intention. We tried to mimick the GP's daily practice of patient selection. In this way, we were not surprised to find penicillin to be more effective than in the population of Little et al, who probably included many patients with a viral infection.[5] Interestingly, their 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 beneficially influenced the duration of sore throat in these patients. Contrary to Little et al, we are not worried that the artificial use of throat-swabs and medication-tray would bias the recording of symptoms in the diary. How can bias play a role if randomised patient-groups are compared? In case the compliance was artificially improved by the use of a medication-tray and a second consultation, the outcome of our study should stimulate doctors even more to convince patients to complete the 7-day course. 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 appeared to be at the same level as in some 1950-studies[6] may again be explained by the strict inclusion criteria we used, selecting probably the most ill patients, most of them having a streptococci-positive throat swab. We agree with Little et al that the population studied should be taken into account when generalising the findings. However, because we found significant 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 the selection criteria we used in our study and that are also used in Dutch daily practice to other routine settings, such as UK primary care. The fear of Fleetcroft and Little is that penicillin will be used as a routine drug in a routine setting, thus leading to medicalized patients and resistant strains. We share their fear, but believe that doctors and patients can only make a well-balanced decision when they are informed not only about the costs and adverse effects of antimicrobial therapy, but also about the benefits.[7] [8] Sjoerd Zwart Alfred Sachs Gijs Ruijs Jan Gubbels Arno Hoes Ruut de Melker 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 (accepted for publication). 2 Del Mar C. Sore throats and antibiotics. [editorial] BMJ 2000;320:130-1. 3 Ioannides JPA, Lau J. Can quality of clinical trials and meta-analyses be quantified? [commentary]. Lancet 1998;352:590. 4 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;10:371-7. 5 Little PS, Gould C, Williamson I, Warner G, Gantley M, Kinmonth AL. An open randomised trial of prescribing strategies for sore throat. BMJ 1997;314:722-7. 6 Chamovitz R, Rammelkamp CH, Wannamaker LW, Denny FW. The effect of tonsillectomy on the incidence of streptococcal respiratory disease and its complications. Pediatrics 1960;26:355-67. 7 Bradley CP. Factors which influence the decision whether or not to prescribe: the dilemma facing general practitioners. Br J Gen Pract 1992;42:454-8. 8 Graham A, Fahey T. Sore throat: diagnostic and therapeutic dilemmas. BMJ 1999;319:173-4. |
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