a Department of Paediatrics, Sophia Children's Hospital/University Hospital, Rotterdam, The Netherlands; b Department of Epidemiology and Biostatistics, Erasmus University, Rotterdam, The Netherlands; c Juliana Children's Hospital, The Hague, The Netherlands; d Department of Paediatrics, 't Groene Hart Hospital, Gouda, The Netherlands; e Department of Paediatric Radiology, Sophia Children's Hospital/University Hospital, Rotterdam, The Netherlands
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Abstract |
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Introduction |
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Co-amoxiclav is frequently given as treatment for LRTI in children. Compliance is often a problem as it is usually given three times a day for 10 days.57 Because of the pharmacokinetic profile it is possible to administer azithromycin in a once-daily dose for 3 days. This is a great advantage in the treatment of ambulatory patients and, in the case of children, also for the parents.
The purpose of the current study was to compare the clinical efficacy, safety and tolerability of a 3 day course of azithromycin with a 10 day course of co-amoxiclav in children with acute LRTI. This is the first study of this kind to use a double-blind, double-dummy design.
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Materials and methods |
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The study was designed as a multicentre, randomized, double-blind, double-dummy, comparative trial of the clinical efficacy of azithromycin versus co-amoxiclav in the treatment of children with acute LRTI.
The ethical review boards of all eight participating institutions approved the study protocol. Informed consent was obtained from the parents of all children.
Patients
Patients (age 3 months12 years) with community-acquired LRTI were included between June 1995 and December 1998. One university hospital, the Sophia Children's Hospital, Rotterdam, and seven regional hospitals in the southwestern Netherlands participated in the study.
The diagnosis of LRTI was based on the presence of respiratory signs and symptoms in combination with a positive chest radiograph showing consolidation of at least a part of a lung lobe without loss of volume, or clinical evidence of LRTI according to the following definition: rectal or oral temperature 38°C, cough, leucocytosis >10000 cells/mm3 or 15% band forms and rales, rhonchi or signs of consolidation on physical examination.
Patients were excluded on the basis of the following: complaints of LRTI longer than 1 week, weight >40 kg, need for parenteral therapy, congenital malformations of the respiratory tract, foreign body aspiration, cystic fibrosis, bronchopulmonary dysplasia, congenital or acquired heart disease, severe retardation, immunodeficiency disorders, known hypersensitivity to ß-lactams or macrolides, previous participation in this study, treatment with any investigational drug or azithromycin within 1 month before enrolment or concurrent therapy with ergotamine or digitalis glycosides.
Study drug
Patients were assigned randomly to treatment with oral azithromycin suspension (10 mg/kg/24 h) in a single dose for 3 days or co-amoxiclav suspension (45/11.25 mg/kg/ 24 h) tds for 10 days. Blinding of the study was maintained with matched placebo suspension: patients in the azithromycin group received co-amoxiclav placebo suspension tds for 10 days. Patients in the co-amoxiclav group received azithromycin placebo suspension in a single dose on the first 3 days.
Each centre was provided with study medication by the sponsor of this study (Pfizer B. V., Capelle a/d Yssel, The Netherlands). The combinations of azithromycin and co-amoxiclav active/placebo had been allocated randomly in blocks of six. Randomization was done at Imro Tramarko, Berghem, The Netherlands.
Clinical evaluation
Clinical signs and symptoms of LRTI were recorded before the start of treatment on day 1 (visit 1). Changes were monitored on days 35 (visit 2), on days 1013 (visit 3) and on days 2530 (visit 4). At all follow-up visits, adverse events, use of concomitant drugs and compliance with study medication were assessed.
Haemoglobin, haematocrit, white blood cell count and differential, platelet count and C reactive protein or sedimentation rate were determined at visits 1 and 4. At visit 1, oxygen saturation was measured transcutaneously.
Chest radiographs were obtained at visits 1 and 4. A paediatric radiologist (S. G. F. Robben) reviewed all radiographs.
On visits 2, 3 and 4, the patient's response to treatment was classified by the investigator as cured, clinically improved or failure. Cure was defined as disappearance of clinical signs and symptoms within the treatment period; improved was defined as subsiding of signs and symptoms but with incomplete resolution; failure was defined as unchanged or worsened clinical signs and symptoms. Patients in whom, according to the treating physician, it was necessary to stop the study medication and to commence other treatment were also classified as failures. Temperature was recorded twice daily by parents, taken rectally in the early morning and the evening. Patients were considered free of fever when their temperature was <37.5°C on two consecutive occasions. One month after the last visit, the parents were contacted by phone to inquire after the condition of the patient.
All outcome data for individual patients were reviewed before breaking the treatment code.
Safety
At visits 2, 3 and 4, adverse events were recorded and classified as mild, moderate, severe or life-threatening. The relationship to treatment was recorded as possibly related, probably related, certainly related, probably not related or certainly not related.
Compliance
The parents registered the doses of medication used on a diary card. Intake of <80% of the active medication was considered as non-compliance.
Bacteriology and virology
Blood cultures were taken. Sputum cultures were obtained when the child was able to expectorate sputum. The cultures were processed according to standard procedures. A nasopharyngeal aspirate was taken on the day of admission and 2530 days later, using a standard procedure with 0.9% sodium chloride and a disposable mucus extractor (Unoplast; Maersk Medical, Denmark). Direct viral immunofluorescence assays were performed for respiratory syncytial virus (RSV), adenovirus, influenza A and B virus and parainfluenza virus 1, 2 and 3 followed by virus isolation for these viruses and also cytomegalovirus. PCR procedures were performed for M. pneumoniae and C. pneumoniae.
Serum samples collected at admission and 2530 days later were used for serological analysis to detect antibodies against RSV, parainfluenzavirus type 13, adenovirus, influenza A and B virus, M. pneumoniae and C. pneumoniae. A four-fold antibody rise measured by complement fixation test or specific IgA, IgM and IgG enzyme immune assays between the sera was considered diagnostic.
Statistical analysis
The primary endpoint was cure or clinical improvement at visit 3 (1013 days). Equivalence of both treatments was considered to be shown if the lower limit of the two-sided 90% confidence interval for the difference (azithromycin minus co-amoxiclav) of percentages of patients who reached the endpoint was greater than 10%. With an assumed cured/improved percentage of 95%, with 118 patients the power of the study to demonstrate equivalence equals 80%.8 Percentages were compared using Fisher's exact test. Number of days until disappearance of fever and number of adverse events per patient were compared using the MannWhitney test. The limit of statistical significance was set at P = 0.05 (two-sided).
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Results |
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Fifty-six and 54 patients, respectively, were treated with azithromycin and co-amoxiclav. The two treatment groups were comparable (Table I). The median age in the group treated with azithromycin was 3.8 years versus 2.7 years in the group treated with co-amoxiclav. This difference was not statistically significant.
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The proportion of patients who were cured or improved at visit 3 (1013 days) was 91% for azithromycin and 87% for co-amoxiclav (Table II). Two patients, one in each group, were not evaluable for clinical outcome at visit 3. No statistically significant difference (P = 0.55) was observed between the two therapy groups in terms of clinical outcome at visit 3, with 90% confidence interval for the difference (azithromycin minus co-amoxiclav) of the cured/ improved percentage ranging from 6% to +14%.
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There was no statistically significant difference in clinical outcome at visit 3 in the azithromycin group (P = 0.34) or the co-amoxiclav group (P = 1.00) when we compared children older than 5 years with the younger ones.
On visit 4 (2530 days), the percentage of cured/ improved patients was 90% in the azithromycin group and 86% in the co-amoxiclav group (Table II). One of these cured patients, in the azithromycin group, developed a respiratory tract infection with bronchial obstruction 2 weeks after the last visit.
Seventy-four (77%) diary cards of the 96 patients who were cured/improved at visit 3 and who had fever at entry into study were evaluable for analysis of the temperature response. The median time for the temperature to return to normal in these patients was 3 days in the azithromycin group (n = 39). The median time in the co-amoxiclav group (n = 35) was 2 days (Table III). This difference was not statistically significant (P = 0.08).
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There was no difference in clinical outcome between children presenting with or without a consolidation on the chest radiograph.
Ninety-four (85%) diary cards were available to assess compliance (Table III). One patient had taken only 30% of the co-amoxiclav. She was improved clinically on visit 2 after 2 days of therapy, with coughing as the only complaint. On visit 4, she was clinically cured. Compliance was adequate for all other patients.
Only patients who received at least one dose of study medication were included in the safety analysis. A total of 117 patients was analysed, because one patient (withdrawal of informed consent) did not receive any study medication. Fifty-six per cent (33/59) of the patients treated with azithromycin reported adverse events compared with 71% (41/58) in the co-amoxiclav group (P = 0.13) (Table III). The total number of adverse events in the azithromycin group was 47 and in the co-amoxiclav group 70; corresponding to mean numbers of 0.8 and 1.2 per patient, respectively. This difference was statistically significant (P = 0.04). Adverse events scored by the research physician as related (possible, probable, certain) to the study medication occurred in 24% versus 47% in the azithromycin- and the co-amoxiclav groups, respectively (P = 0.01). This difference is due largely to a significantly (P = 0.005) increased incidence of gastrointestinal complaints in the co-amoxiclav group (43 versus 19%). The incidence of other relevant adverse events (rash, fever) did not differ significantly between the groups. No serious adverse events related to the study medication occurred.
In both groups a pathogen was identified in about 55% of patients. There were no differences between the two groups concerning microorganisms (viral, bacterial, atypical, mixed) that possibly caused disease. Table IV shows the aetiological agents found in both groups.
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Discussion |
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The clinical outcome in our study is comparable with those reported in previous studies.5,9 In this, the first double-blind study, a 3 day course of azithromycin showed efficacy equal to a longer, more complex regimen of co-amoxiclav in children with LRTI.
Previous studies showed that azithromycin is well tolerated in children, with adverse events rates of 627%.1012 Children in the azithromycin group in this study experienced adverse events related to the medication in 24% of cases. It is not clear why the co-amoxiclav group reported such a high percentage (47%) of medication-related adverse events, as in previous studies this ranged from 11 to 31%.5,10,11,13
It is still difficult to detect rapidly the causative pathogen in children with acute LRTI and antibiotic treatment in children with LRTI is almost always empirical. Azithromycin is one of the newer macrolides, and provides a good choice for the treatment of LRTI in children. Furthermore, administration of azithromycin is attractive because of once-daily dosing and the short duration of therapy.
We conclude that a 3 day course of azithromycin (three doses) is as effective as a 10 day course of co-amoxiclav (30 doses) in the treatment of LRTIs in children. Azithromycin is better tolerated than co-amoxiclav and may be preferable to co-amoxiclav in children with LRTI because of its more convenient and shorter regimen.
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Acknowledgments |
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Notes |
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References |
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Received 28 July 2000; returned 26 October 2000; revised 9 November 2000; accepted 28 November 2000