a Dijon University Hospital, Hôpital du Bocage, Service des Maladies Infectieuses, 2 boulevard de Lattre de Tassigny, 21034, Dijon; b Abbott France, Rungis Cedex; c Bio-VSM, Vaires-Sur-Marne; d Sanofi-Synthelabo France, Paris, France
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Abstract |
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Methods: Three hundred and forty-nine patients (1240 years) with acute pharyngotonsillitis and a positive Streptococcus A antigen immunoassay test were randomized to receive clarithromycin MR 500 mg od for 5 days or penicillin 590 mg tds for 10 days. Patients were clinically evaluated and a throat swab for culture obtained before treatment, after treatment (day 8 or 13 depending on the treatment arm) and at the follow-up visit (day 30). The main criterion for efficacy was the bacteriological cure rate after treatment.
Results: Three hundred and forty-nine patients were considered for the intent-to-treat analysis. After treatment, clinical cure rates were 88.1% in the clarithromycin group and 92.4% in the penicillin group, and eradication rates were 82.8% and 83.6%, respectively. There were no statistically significant differences between the two treatments. Three hundred and three (87%) patients had a positive culture before treatment, among which 29 (9.7%) were found to be clarithromycin resistant. Two hundred and thirty-nine patients were clinically and bacteriologically evaluable for per protocol analysis. After treatment, clinical cure rates were 95.2% in the clarithromycin group and 97.3% in the penicillin group, and eradication rates were 94.4% and 92%, respectively. No statistically significant difference was shown. Adverse events occurred in 46 patients of the clarithromycin group and 31 of the penicillin group (with no statistical difference). Most of them were of mild or moderate severity.
Conclusion: Clarithromycin MR administered once daily for 5 days is as safe and effective as penicillin V administered three times a day for 10 days in the treatment of GABHS pharyngitis.
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Introduction |
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Macrolide antibiotics are considered alternative drugs of choice, particularly in patients allergic to ß-lactams. However, the resistance rates of GABHS to macrolides in Europe, which were stable at <5% until the mid-1990s,15 have increased significantly in several countries such as Spain16,17 and Italy.18 In France, the rate of macrolide resistance is c. 58%.13,19
In three comparative studies,2022 clarithromycin has been clinically and bacteriologically as effective as erythromycin and penicillin V when prescribed for 10 days.
A modified release form of clarithromycin tablet (500 mg) was developed by Abbott Laboratories (Abbott Park, IL, USA) to allow patients to take the antibiotic only once a day. When measured against 250 mg bd clarithromycin, the modified release form of the antibiotic (clarithromycin MR) achieved comparable pharmacokinetic data23 [area under the curve (AUC), maximum concentration].
The current tendency is to try to define simpler therapeutic regimens using more recently developed drugs, which allow a shorter treatment duration and require fewer doses per day (compared with penicillin), in order to improve compliance and, therefore, bacteriological efficacy. For that reason, we evaluated the efficacy and tolerability of a short-term (5 day), single daily dose treatment for streptococcal pharyngitis in a Phase III trial of clarithromycin MR, compared with conventional 10 day treatment with penicillin V.
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Patients and methods |
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French general practitioners performed the study. To be included in the study, patients had to be between 12 and 40 years of age. In the absence of cough or rhinitis, they had to have an elevated temperature with at least two of the following symptoms: sore throat or painful swallowing, a tonsillopharyngeal erythema or exudate, or a sensitive cervical lymph node. A positive group A Streptococcus antigen immunoassay test (StrepA Test with OBC, Abbott Laboratories) was also required for inclusion in the study.
Patients were excluded if they had signs of serious or chronic cardiovascular, pulmonary, renal, hepatic, metabolic, gastrointestinal, neurological, endocrine, neoplastic or psychiatric disease that was not controlled by treatment. Patients could not be breast-feeding or present the risk of pregnancy, as determined by a negative ß-hCG test and the use of contraceptives. Patients were also excluded if they: had received an antibiotic within the previous 2 weeks or a delayed-action penicillin within the previous 6 weeks; were taking corticosteroids or either terfenadine, astemizole, rye ergot alkaloids, cisapride or pimozide; or were taking triazolam, midazolam, phenytoin, digoxin, warfarin, theophylline, cyclosporin or carbamazepine without monitoring. Patients who had an allergy to macrolide or ß-lactam antibiotics, hepatic or renal insufficiency, pharyngeal or tonsillar ulcers, membranes or abscess, or herpangina, dermatological signs of scarlet fever, a history of cardiac valvular disease or acute rheumatic fever or associated infection requiring another antibiotic were excluded. Patients who weighed <40 kg or >100 kg, or had participated in another clinical trial in the previous 8 weeks were also excluded.
Study design
The study was an open comparison between the two antibiotics, following the study design used for the same indication in similar studies.4,12,13 Patients were randomized to receive one tablet containing 500 mg of clarithromycin MR once a day for 5 days or one tablet containing 590 mg (1 million units) of penicillin V three times a day for 10 days. To reduce the effects of the open study approach, bacteriological efficacy (which was the main efficacy criterion) was read blindly by the bacteriologist and independently of clinical symptoms.
Patients were scheduled for three further visits: a telephone call (visit 2) on day 3 to confirm that the clinical course was satisfactory and the drug was well tolerated; a visit after treatment (visit 3) on day 8 ± 1 or 13 ± 1 (depending on the treatment group) to assess bacteriological and clinical efficacy; and a follow-up visit (visit 4) on day 30 during which clinical efficacy and tolerability were evaluated.
Throat samples obtained at the enrolment visit and visits 3 and 4 were mailed the same day for culture to the central laboratory (Laboratoire de Biologie Medicale BIO VSM, Vaires-sur-Marne, France) using Amies transport medium (TGV-AER; Bio-Rad, Marnes-la-Coquette, France). Swabs were plated on 5% sheep blood agar (bioMérieux, Marcy l'Étoile, France), incubated anaerobically and examined at 24 and 48 h. ß-Haemolytic streptococcal isolates were typed with group A identification latex reagent (bioMérieux). Strains of GABHS were tested for susceptibility to penicillin G, erythromycin, clarithromycin and lincomycin by standard disc diffusion test and stored frozen at -70°C. MICs of clarithromycin against susceptible strains were further determined using the NCCLS microdilution procedure.
Tolerability was evaluated by reporting all adverse events. An adverse event was defined as any adverse manifestation in a patient who was taking the trial medication, whether or not it was related to the drug, and which occurred while taking the medication or within 30 days of discontinuing the treatment.
The investigator evaluated compliance by counting the tablets returned at the post-treatment visit and by reading a diary in which each patient recorded medication administration.
The Dijon Advisory Committee for the Protection of Persons in Biomedical Research approved the protocol for this study. The study was conducted in accordance with the ethics principles of the Declaration of Helsinki. Each patient (or both parents of a minor patient) signed a free, informed, written consent during the first visit of the trial.
Evaluation criteria
To be evaluable clinically, a patient had to have tonsillopharyngitis that was documented on clinical examination and attributed to GABHS by culture. Clinical signs and symptoms had to be evaluated at visits 1 and 3. The patient could not have received any medication capable of influencing the results of observation for 6 weeks before the beginning of the trial and until visit 4. The patient had to receive the treatment assigned at random and had to have taken at least 80% of the trial treatment. To be evaluable bacteriologically, a patient had to be clinically evaluable and have a culture of a throat swab obtained at visit 3 at least 48 h after the last dose of the trial drug.
Bacteriological cure was defined as eradication of GABHS as demonstrated by a negative culture on visit 3. Bacteriological failure was indicated by the presence of GABHS (positive culture) on visit 3 or any unplanned visit before visit 3. A negative culture on visit 3 followed by a positive culture on visit 4 was defined as bacteriological recurrence. A bacteriological response that could not be determined (e.g. transport delayed, swab not placed in transport medium) was classified as indeterminate.
The signs of infection at the beginning of treatment were compared with those observed at visits 3 and 4 to assess clinical response. Clinical cure was defined as the disappearance of signs and symptoms that were present at visit 1. Pre-treatment signs and symptoms that were not improved or were aggravated indicated treatment failure. Signs and symptoms that reappeared or were aggravated at visit 4 indicated clinical recurrence. Any case for which response to treatment could not be evaluated clinically and for which the reason was recorded on the case report form (e.g. concomitant infectious disease, evaluation carried out too late) was indicated as indeterminate.
Statistical methods
The intent-to-treat (ITT) analysis considered all patients who had taken one dose of the treatment; the per protocol (PP) analysis considered all evaluable patients. All patients who had taken at least one dose of treatment had to be included in the tolerability analysis, which encompassed all reported adverse events.
The principal criterion for efficacy analysis was the rate of eradication of group A Streptococcus after treatment (visit 3).
Statistical analysis was performed using the 2 test or Fisher's exact test (qualitative variables) and ANOVA (quantitative variables). The number of evaluable patients required was 236 (
= 5%, 1 - ß = 80%).
For efficacy data, an additional analysis of equivalence was carried out (Dunnet and Gent test, = 10%,
= 5%, 1 - ß = 70%).
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Results |
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Patients were recruited from 109 GPs. Three hundred and fifty-one patients were selected from November 1997 to June 1999, and 349 patients actually received treatment and were considered for the ITT analysis at visit 3: 177 in the clarithromycin group and 172 in the penicillin V group.
Of these 349 patients, 16 did not undergo the visit 3 evaluation: nine in the clarithromycin group and seven in the penicillin group. The most common reason was that the patients had a negative culture at visit 1, but dropped out of the study before visit 3 and no post-treatment evaluation was carried out (six patients in the clarithromycin group, four in the penicillin group). Four patients did not meet the selection criteria, one patient moved after visit 2 (lost to follow-up) and one patient stopped treatment at day 2 because of an adverse event (abscess). This adverse event was not related to the study drug (clarithromycin group).
Three hundred and three patients had a positive culture for GABHS at visit 1 and were considered for the modified ITT analysis at visit 3: 151 patients in the clarithromycin group and 152 in the penicillin V group. The same population was considered for the analysis of clinical and bacteriological efficacy at visit 4, as the patients who had a negative culture before treatment had to drop out of the study at visit 3.
Of these 303 patients, 64 were not evaluable: 29 (9.7%) patients had a clarithromycin-resistant GABHS at the time of inclusion and 35 (11.6%) had a major deviation from protocol (11 in the clarithromycin group, 24 in the penicillin group). The most common reason for major devia-tion was that the throat swab at visit 3 had been obtained too soon: 16 patients in the penicillin group had a post-treatment visit scheduled and performed on day 12 but received their last dose of treatment on day 11 (day 1 was the first day the dose was administered). Two hundred and thirty-nine patients were finally eligible for the PP analysis at visit 3.
Patients characteristics
The demographics were similar in the two study arms and there were no significant differences between the two treatment arms regarding clinical history (Table 1).
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Of the 303 GABHS strains that were isolated before treatment, 29 were resistant to clarithromycin (9.6%), and none was resistant to penicillin V. The MIC50 and MIC90 of clarithromycin against susceptible strains were 0.016 and 0.032 mg/L, respectively.
Efficacy
In the ITT analysis, clinical cure at visit 3 was obtained in 156 (88.1%) patients in the clarithromycin group and 159 (92.4%) in the penicillin V group (Table 2). There were 10 (5.6%) clinical failures in the clarithromycin group and six (3.5%) in the penicillin V group. Eradication of GABHS was obtained in 125 (82.8%) cases in the clarithromycin group and 127 (83.6%) in the penicillin V group. Twelve (7.9%) patients in each group exhibited bacteriological failure. There was no statistically significant difference between the two treatment groups for clinical (P = 0.868) and bacteriological efficacy (P = 0.999).
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In the PP analysis, 120 (95.2%) patients in the clarithromycin group achieved clinical cure at visit 3 compared with 110 (97.3%) in the penicillin V group (P = 0.505) (Table 3). Six (4.8%) patients in the clarithromycin group and three (2.7%) in the penicillin group failed clinically. GABHS eradication was obtained in 119 patients (94.4%) in the clarithromycin group and 104 (92.0%) in the penicillin V group. Seven (5.6%) bacteriological failures were found in the clarithromycin group and eight (7.1%) in the penicillin V group. No statistically significant difference was shown for clinical (P = 0.505) and bacteriological efficacy (P = 0.598).
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Safety
All 349 patients who took at least one dose of treatment were evaluated for safety. Seventy-seven patients (22.1%) had at least one adverse event, 46 (26%) in the clarithromycin group and 31 (18%) in the penicillin V group. There was no statistically significant difference between the two treatment groups (P = 0.073). The most frequently reported events in the clarithromycin group were gastrointestinal.
A relationship between adverse events and treatment was excluded in 55.9% of patients in the clarithromycin group and in 52.4% in the penicillin V group. Only one serious adverse event was reported, in a 19-year-old patient (clarithromycin group), who was hospitalized for acute lobar pneumonia. This event was not related to treatment.
Two patients dropped out of the study because of intolerance; one patient in the clarithromycin group had an allergic skin reaction, and one patient in the penicillin V group had moderately severe nausea and alteration of taste.
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Discussion |
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Since 1988, studies have shown that shorter regimens with other antibiotics provide eradication rates equal or superior to those obtained with penicillin V in both adults and children.413,24,25 It was also observed that eradication rates with penicillin V or its comparators were usually lower in children compared with those seen in adults, with no obvious explanation. In 1997, a study evaluated the efficacy of a 5 day treatment with the paediatric formulation of clarithromycin (7.5 mg/kg bd) in 528 children. Bacteriological cure rates were 94% in the clarithromycin group and 78% in the penicillin group (P < 0.001).14
Several studies have been performed in France with a similar design, and led to the approval of shorter treatments. Six day amoxicillin treatment is effective in adults, with a bacteriological cure rate of 92% compared with 92.6% in the penicillin V group,4 as well as in children, with a bacteriological cure rate of 83.7% compared with 85.3% in the penicillin V group;5 5 day josamycin is effective in adults, with a bacteriological cure rate of 93% compared with 89% in the penicillin V group,12 and in children, with a bacteriological cure rate of 82% compared with 80% in the penicillin V group.25 Three day azithromycin is effective in adults, with a bacteriological cure rate of 89.6% compared with 91.6% in the penicillin group,13 but several clinical studies assessing a 3 day regimen in children found azithromycin to be significantly inferior to the reference treatment at a dosage of 10 mg/kg/day.2628 One of the possible explanations was that the dosage was inadequate, as the results were better with 12 mg/kg/day than with 10 mg/kg/day. A recent study conducted in France24 showed that for azithromycin, 20 mg/kg/day is the effective dosage when a 3 day regimen is considered: the bacteriological cure rate was 94.2% with 20 mg/kg/day, 57.8% with 10 mg/kg/day and 84.2% with penicillin V given for 10 days.
This Phase III trial was conducted in patients between 12 and 40 years of age. One hundred and nine investigators enrolled 351 patients over a 19 month period. Although a large number of investigators was also reported during similar studies,4,12,13 the methods of selection of the study population could be rightly questioned. In France, 60 000 GPs see approximately 1 million patients with pharyngitis per year, i.e. 150 pharyngitis cases per GP, of which 40 are due to GABHS. However, in practice the enrolment possibilities are very limited by strict selection criteria, major difficulties when the patients are seen at home, patient refusals, the necessity of obtaining the signature of both parents on the consent form for patients under 18 years of age, the obvious lack of time during periods of epidemics, etc. It is very unlikely that patients were selected on other criteria.
The principal objective of the study was to compare the rates of eradication of GABHS achieved in each treatment group at visit 3, which was planned at least 48 h after the last dose of the treatment. This criterion was very strictly applied to the assessment of the patient's evaluability, and the time of last dose verified for each case. The most common reason for major deviation was that the throat swab at visit 3 had been obtained too soon (17/35 major deviations). The other important reason for non-evaluability was the isolation of a clarithromycin-resistant strain before therapy in 29 patients (9.7%).This rate is similar to those obtained in recent studies on macrolide resistance in France.19 It is clinically relevant, but remains lower than those observed in some other European countries such as Spain and Italy.1618 The data obtained in France were reviewed recently.29
The clinical and bacteriological results for the patients infected with resistant strains in the clarithromycin group were not correlated (Table 4): despite a low rate of bacteriological efficacy (28.6%), a clinical cure was obtained in 10 of 14 patients (71.4%). All these patients were, of course, included in the ITT analysis.
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Statistical testing showed that bacteriological and clinical efficacy of clarithromycin MR administered for 5 days was similar to that of penicillin administered for 10 days. No statistically significant difference in bacteriological response was detected after treatment (visit 3). Clinical signs and symptoms resolved in patients with both regimens, and no post-streptococcal complication was reported. A bacteriological evaluation was also performed at visit 4, though it was known that recurrence 3 weeks following treatment could be due to many factors, which are more indicative of the epidemiology of the disease than of the efficacy of the antibiotic used. These factors include prevalence of the organisms in the community and exposure of the patients to these organisms.30
Adverse events occurred in 46 patients of the clarithromycin group and 31 of the penicillin group (with no statistical difference). Most of them were of mild or moderate intensity. No drug-related serious adverse event was notified during the trial, and only two patients interrupted their treatment because of an adverse event (one in each group).
In summary, this study showed that clarithromycin MR 500 mg administered for 5 days for pharyngitis due to GABHS is as effective and well tolerated as the reference treatment, penicillin V administered for 10 days. In addition, the shorter treatment duration and once-daily dosing increase the convenience for patients.
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Acknowledgements |
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Notes |
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References |
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Received 29 May 2001; returned 8 August 2001; revised 21 September 2001; accepted 16 October 2001