An open comparative study of azithromycin versus cefaclor in the treatment of patients with upper respiratory tract infections

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1 Journal of Antimicrobial Chemotherapy (1996) 37, Suppl. C, An open comparative study of azithromycin versus cefaclor in the treatment of patients with upper respiratory tract infections B. O'Doherty Merrion Lodge, 4 Charlotte Row, Gorey, County Wexford, Wexford, Eire Azithromycin and cefaclor were compared for the treatment of acute otitis media, streptococcal pharyngitis/tonsillitis, or sinusitis in an open multicentre study conducted in 53 adults. At the end of therapy (day 11-15), 228/245 (93%) patients treated with azithromycin 5 mg once daily for 3 days and 233/241 (97%) treated with cefaclor 25 mg given three times daily for 1 days were considered to have responded satisfactorily (cured or improved). In bacteriologically evaluable patients with pharyngitis/ tonsillitis, Streptococcuspyogenes was eradicated in 116/117 (99%) azithromycin-and in 115/119 (97%) cefaclor-treated patients at day 11-15; one patient in each group had become reinfected after initial eradication of the pathogen. When followed up on day 25-3, S. pyogenes infection had recurred in 5/15 (5%) azithromycin and 4/18 (3%) cefaclor patients who had responded satisfactorily at day 11-15, and whose baseline pathogen had been eradicated. Of these patients, two in the azithromycin and one in the cefaclor group also relapsed clinically; the others remained asymptomatic. Patients tolerated both treatments well; treatment-related adverse events were recorded in 11 % of the 267 azithromycin- and 1% of the 263 cefaclor-treated patients assessed for safety. One azithromycin patient and five cefaclor patients withdrew because of adverse events. The results of the study show that a 3-day regimen of azithromycin, given once daily, is as effective and well tolerated as a multiple-daily, 1-day cefaclor regimen for the treatment of upper respiratory tract infections in adults. Introduction Upper respiratory tract infections (URTIs) are very common. Acute sore throat or infectious pharyngitis/tonsillitis, although often viral in nature, when usually bacterial in origin is associated with Streptococcus pyogenes. Two other URTIs encountered frequently in clinical practice are otitis media and sinusitis, although the former is predominantly a disease of childhood. By contrast, sinusitis occurs mainly in adults. The pathogens implicated in both of these diseases are similar; the most common are Streptococcus pneumoniae and Haemophilus influenzae, with Moraxella catarrhalis assuming increasing importance. Other bacteria responsible for URTIs include Staphylococcus aureus and S. pyogenes, and, in about 5% of young adults, primary sinusitis is due to Chlamydia pneumoniae. In the treatment of pharyngitis/tonsillitis, the aim of therapy is not only the elimination of the clinical signs and symptoms, but also the eradication of the pathogen to avoid recurrence. For many years, prolonged treatment with penicillin V, given up to four times daily for 1 days had been thought necessary to achieve bacteriological clearance as well as clinical control of the symptoms. Standard therapies for other 3O5-7453/96/37CO $12./ The British Society for Antimicrobial Chemotherapy

2 72 B. O'Doherty similarly complex and of long duration: for example, otitis media is often treated with a 1-day regimen of amoxycillin or ampicillin given three or four times daily. Not all patients, however, are given penicillins; those with hypersensitivity to penicillin, or in whom treatment has been unsuccessful, because of microbial resistance are often treated with erythromycin. Erythromycin is, however, associated with a high incidence of gastrointestinal side-effects (Pilot & Qin, 1988; Anderson et al., 1991; Pechere, 1993). Azithromycin is structurally related to erythromycin, but has several advantages compared with the parent compound, which requires multiple daily dosing over 1 days to be clinically effective. The introduction of a methyl-substituted nitrogen at position 9a of the lactone ring (Bright et al., 1988) to form an azalide results in an improvement in the pharmacokinetic profile of azithromycin compared with erythromycin (Girard et al., 1987). An important feature of azithromycin is its ability to achieve high tissue concentrations, which are frequently more than 1 times those in serum. One study detected maximum azithromycin levels in tonsillar tissue of 4.5 mg/kg after the administration of two 25-mg doses given 12 h apart (Foulds et al., 1991). The study also showed that tissue levels decline very slowly: the tissue half-life is 76 h. Extrapolation of these data has established that once-daily dosing with 5 mg azithromycin on 3 consecutive days will result in the tonsillar levels of azithromycin being maintained at above 2 mg/l for over 1 days. The chemical modification, however, does not compromise bacteriological activity. Azithromycin is up to eight times more effective than erythromycin against H. influenzae, and the azalide also possesses good activity aginst M. catarrhalis, with an MIC*, of less the 1 mg/l (Arnoff, Laurent & Jacobs, 1987; Retsema et al., 1987; Dunkin, Jones & Howard, 1988; Hardy et al., 1988). Furthermore, azithromycin is active against S. pyogenes (MIC*, mg/l) (Arnoff, et al., 1987, Retsema et al., 1987; Hardy et al., 1988). Thus, concentrations in tissues over 1 days exceed the MICs of many important respiratory pathogens (Foulds & Johnson, 1993). Cephalosporins are another alternative to the penicillins for the treatment of URTIs. This is on the basis of their greater /J-lactamase stability and wider antibacterial spectrum. Thus, cephalosporins can be more effective than penicillins against mixed infections or when the indigenous flora includes /Mactamase-producing organisms. Cefaclor is a second-generation cephalosporin with greater activity against H. influenzae than earlier compounds within this class of antibacterial agents. A 1-day regimen of cefaclor has been shown to more effective than a comparable penicillin V regiment for the treatment of pharyngitis (Stillerman, 1986; Carbon, 1988; Cohen et al., 1991) and otitis media (McLinn, 1988; Nelson, 1988, Valdvogel, 1988). The study described below was undertaken to assess the efficacy and safety of azithromycin given once daily for 3 days and to compare it with those of cefaclor administered three times daily for 1 days in the treatment of acute upper respiratory tract infections in adults. Patients Patients and methods The design of this study was approved by local Ethics Committees. Patients of either sex, 12 years of age or older with acute otitis media, pharyngitis/tonsillitis, or maxillary

3 URT1 treatment: azithromycin vs cefaclor 73 sinusitis were recruited for the study. Diagnoses were made on the basis of clinical history, physical findings and/or isolation of a pathogen. For a diagnosis of otitis media, a patient had to possess at least two of the following signs of symptoms: earache; hyperaemia of the tympanic membrane; diminished or absent light reflex of the tympanic membrane; and bulging and/or perforation of the tympanic membrane. A diagnosis of pharyngitis/tonsillitis, based on the patient reporting a sore throat and difficulty in swallowing, had to be confirmed by isolation of S. pyogenes from the throat at the time of entry to the study. The diagnosis of maxillary sinusitis made on the basis of pain, tenderness and purulent nasal discharge was confirmed by X-ray. Women who were pregnant or breast feeding or of child-bearing potential but not using adequate contraception (oral or implanted contraceptives, intrauterine device or diaphragm) were excluded from the study. Patients who were terminally ill or had any condition that was likely to preclude completion of the study were also excluded, as were patients with fibrocystic disease, or with a gastrointestinal condition, including a history of chronic diarrhoea, a peptic ulcer, or a gastrectomy, that could affect drug absorption. Concurrent medication with ergotamine, cyclosporin, or digitalis glycosides was not permitted, and patients hypersensitive to azithromycin, other macrolides, or cefaclor were not enroled. Other reasons for exclusion were concurrent infections requiring other antimicrobial therapy and dependency on drugs or alcohol. No patient was included in the study if they had received an investigational drug in the previous month, or another antimicrobial agent in the previous two weeks; the only exception was if there was documented microbiological evidence of failure. Treatment Patients were randomly allocated to oral treatment with either azithromycin or cefaclor. Patients assigned to azithromycin treatment received two 25 mg capsules once daily (total daily dose 5 mg) for 3 consecutive days. Patients within the cefaclor treatment group were treated with a single 25 mg tablet three times each day (total daily dose 75 mg) for 1 days overall. Assessment of clinical and bacteriological efficacy The first day of study treatment was day 1. All patients were assessed before treatment and between days 5-9 and after the start of treatment. Changes in clinical symptoms of infection relevant to each diagnosis fever, irritability, malaise, purulent nasal discharge, sore throat, earache and localized tenderness were monitored at each visit. In addition, throat swabs, nasopharyngeal swabs, or exudates, as appropriate, were collected for bacterial culture and for sensitivity testing by the Kirby-Bauer disc diffusion technique (Bauer et al., 1966). Pathogens were considered to be susceptible to azithromycin if they had an MIC <, 2 mg/l, of intermediate susceptibility if the MIC was 4 mg/l and resistant if the MIC was ^8 mg/l. Pseudomonas aeruginosa, Proteus spp. (except Proteus mirabilis), Morganella spp. and Serratia spp. were considered to be resistant, irrespective of the results of susceptibility testing. Any patient with one of these pathogens at baseline was considered not to be bacteriologically evaluable. At the assessment on day 11-15, clinical response was categorized as cured, improved, failed, or relapsed. 'Cured' was defined as the disappearance of all signs and symptoms of infection; 'improved' as improvement or partial disappearance of all signs and

4 74 B. O'Doherty symptoms; 'failed' as no change or worsening; and 'relapsed' as an initial improvement followed by a worsening, or a recurrence, of signs and symptoms of infection. Bacteriological response was also evaluated at the end-of-therapy assessment (i.e. between days 11 and 15). The baseline pathogen was considered to have been 'eradicated' if it was not isolated upon repeat sampling, or if, because of a clinical cure, there was no material for culture (except in pharyngitis/tonsillitis patients). 'Persistence' was defined as the presence of the baseline pathogen after treatment and 'recurrence' or 'reinfection' as the eradication of the baseline pathogen followed by its reappearance. If an organism was present before or after treatment that was not considered to be an infective organism, the bacteriological response was classed as 'colonization'. Patients with pharyngitis/tonsillitis had an additional follow-up performed between days 25 and 3 to evaluate clinical response and a specimen was cultured if obtainable to assess bacteriological status. Safety All adverse events, whether observed by the investigator or reported by the patient, were recorded at each visit and classified according to their severity and causative relationship to the study drug. Haematology, blood chemistry and urinalysis were performed on entry to the study and between days 11 and 15. If a patient developed any abnormal laboratory value, he or she was followed up until these values returned to baseline, or to the laboratory normal range. Statistical analysis The clinical response for the two treatment groups was compared by the Cochran-Mantel-Haenszel test based on Ridit scores. Safety data for the two groups were compared using the chi-squared or Fisher's exact test as appropriate. The statistical tests were all two-tailed and were performed at the.5 significance level. Results A total of 532 patients from 38 centres in the United Kingdom and the Republic of Ireland were recruited into the study, and 53 received either azithromycin (n = 267) or cefaclor (n = 263). One patient from each treatment group did not return after being issued with their study medication and these were excluded from all analyses. Demographic characteristics and diagnoses by treatment group are summarized in Table I. There were no significant differences between the treatment groups for any of the demographic variables when these were analysed by diagnosis (P >.5). The percentage of patients (4%) in each group who had concurrent conditions on entry to the study was the same: 17 azithromycin- and 14 cefaclor-treated patients. The respiratory system was the most frequently affected with 34 (13%) azithromycinand 37 (14%) cefaclor-treated patients having concurrent conditions. A total of 253 (134 azithromycin and 119 cefaclor) patients received one or more concomitant medications during the study. The commonest concomitant medications were hormones and their synthetic substitutes (63 azithromycin and 49 cefaclor patients) and agents acting on the central nervous system (44 azithromycin and 46 cefaclor patients). Concomitant

5 URTI treatment: azithromycin vs cefador 75 anti-infectives were administered to 18 azithromycin- and 11 cefaclor-treated patients, who were excluded from evaluation. Twenty-two patients from each treatment group were excluded from clinical evaluation. The commonest reasons for exclusion were post-treatment visits outside the times permitted for evaluation (ten azithromycin and eight cefaclor patients) and failure to return for follow-up evaluations (four azithromycin and three cefaclor patients). Several patients who discontinued treatment because of adverse events were excluded from the clinical analysis (one azithromycin and five cefaclor patients). Three azithromycin-treated patients and one cefaclor group patient were excluded because they had received other antimicrobial therapies within the previous two weeks, and one azithromycin group patient because she had received concurrent antimicrobial therapy. Other reasons for exclusion were premature discontinuation of therapy when no baseline pathogen was found or when the diagnosis was not confirmed (two azithromycin and one cefaclor patient), concurrent illness (one cefaclor patient), lack of compliance by the patient (one cefaclor patient) and withdrawal following the discovery of abnormal hepatic values (one cefaclor patient). A further 232 patients were excluded from bacteriological evaluation, in addition to the 44 patients excluded from the clinical evaluation. The principal reason for exclusion was lack of bacteriological data at baseline (112 azithromycin and 15 cefaclor patients), either because of absence of a culture or failure to isolate a pathogen. No sample for culture was obtained from one patient in each treatment group at the day evaluation. Five patients with pharyngitis/tonsillitis from the azithromycin group had no cultures at the follow-up visit on day There were no baseline susceptibility data on the pathogen for one azithromycin-treated patient. One azithromycin- and three cefaclor-treated patients had a resistant pathogen isolated at baseline. Four patients (one azithromycin and three cefaclor) were excluded because the cultures had been taken from the wrong sites. Table I. Baseline characteristics of patients treated with azithromycin or cefaclor Characteristic Number of patients randomized to treatment received treatment male/female discontinued treatment Patients age (years) mean (±S.D.) range Diagnosis otitis media pharyngitis/tonsillitis sinusitis No. of evaluable for clinical response otitis media pharyngitis/tonsillitis sinusitis Azithromycin / ± Cefaclor / ±

6 76 B. O'Doherty Table II. Assessment of clinical response to treatment with azithromycin or cefaclor at the end of treatment (day 11-15) Diagnosis Clinical response Number (%) azithromycin of patients cefaclor Otitis media Pharyngitis/tonsillitis Sinusitis cured improved relapsed failed cured improved relapsed failed cured improved relapsed failed 33 (63%) 14 (27%) 1 (2%) 4 (8%) 122 (8%) 21 (14%) 5 (3%) 4 (3%) 26 (63%) 12 (29%) 3 (7%) 35 (73%) 11 (23%) 1 (2%) 1 (2%) 122 (78%) 3 (19%) 4 (3%) 22 (59%) 13 (35%) 2 (5%) Clinical and bacteriological efficacy A total of 486 patients were clinically evaluable on days Satisfactory clinical responses (cured or improved) were seen in 228/245 (93%) of azithromycin-treated patients and in 233/241 (97%) cefaclor patients. Likewise, in similar proportions of patients in the two treatment groups, there was eradication of the baseline pathogen: 124/125 (99%) in the azithromycin and 125/129 (97%) in the cefaclor group. The clinical outcomes are presented by diagnosis in Table II. There were no significant differences between the treatment groups in the clinical response for any diagnosis. Otitis media A total of 1 patients with otitis media were clinically evaluable on days 11-15: 52 in the azithromycin group and 48 who received cefaclor. Of these, 9% of azithromycin-treated patients and 96% of cefaclor patients were classified as responding satisfactorily (P =.637). Four azithromycin-treated patients and one patient receiving cefaclor were deemed to be clinical failures, and one patient in each group relapsed. None of the patients with otitis media was bacteriologically evaluable. Pharyngitis/tonsillitis On days 11-15, a total of 38 patients with pharyngitis/tonsillitis were clinically evaluable (152 azithromycin patients and 156 cefaclor patients). In the azithromycin group, 94% of patients showed a satisfactory clinical response compared with 97% in the cefaclor group (^ =.132). 5. pyogenes was isolated at baseline from 117 patients in the azithromycin group and 119 patients in the cefaclor group, and these patients were thus eligible for both clinical and bacteriological assessment. At the day evaluation, S. pyogenes had been eradicated in 116 (99%) azithromycin-treated patients and 115 (97%) patients receiving cefaclor (P =.247). Furthermore, in one patient in each group, S. pyogenes was eradicated followed by reinfection with the same pathogen. The baseline pathogen had

7 URTI treatment: azithromycin vs cefaclor 77 persisted in three cefaclor-treated patients. All, except three of the azithromycin-treated patients, whose pathogens were eradicated were classed as clinically cured or improved, the remaining three had experienced a clinical relapse. Both of the reinfected patients were considered to be clinically cured, and of the three cefaclor patients whose pathogen persisted one was considered clinically cured and the other two were classified as relapsed. When patients who had been classed as clinically cured or improved and in whom the baseline pathogen had been eradicated were assessed at days 25-3, there was recurrence of the S\ pyogenes infection in 5/15 (5%) azithromycin group patients and 4/18 (4%) cefaclor-treated patients (P =.746). The clinical response was still considered to be satisfactory in the majority of these patients. Although four azithromycin- and three cefaclor-treated patients had clinically relapsed at follow-up, only two in the azithromycin group and one in the cefaclor group had a recurrence of the S. pyogenes infection. Sinusitis In total, 41 azithromycin-treated patients and 37 cefaclor group patients with sinusitis were clinically evaluable on days The clinical response was classed as satisfactory in 93% of patients in the azithromycin group, and 95% of cefaclor-treated patients (P =.187). Baseline pathogens were isolated from eight sinusitis patients treated with azithromycin: three were infected with S. pneumoniae, two with 5. aureus and one with S. pyogenes. Pathogens were eradicated in all eight patients, seven of whom were regarded as clinically cured. One patient was deemed to have relapsed despite the eradication of S. pneumoniae. In the cefaclor group, at baseline, S. pneumoniae was isolated from four patients, 5. aureus from three patients, H. influenzae from two patients and 5. pyogenes from one patient. The pathogens were eradicated in 8/1 (8%) of patients. In one patient S. pneumoniae was eradicated, but colonization with H. influenzae occurred, and S. aureus persisted in one patient. Eight of these patients were clinically cured or improved; one failed clinically despite eradication of the pathogen (5. pneumoniae). Safety Adverse events related or possibly related to treatment were recorded in 11 % of patients who received azithromycin and in 1% of cefaclor-treated patients (P =.821). These are summarized in Table III. Several patients experienced more than one adverse event. The majority of the events occurred in the gastrointestinal system: 9.4% of azithromycin-treated patients and 5.7% of patients in the cefaclor group experienced adverse events in this system. Nausea was reported by 3.4% of azithromycin- and 3.8% of cefaclor-treated patients, making it the most frequently recorded specific adverse event. Most of the events were of mild or moderate severity, although events considered to be severe were recorded for six azithromycin- and four cefaclor-treated patients. In the cefaclor group two patients developed a skin rash and one experienced pruritus, whereas no azithromycin-treated patient had any dermatological adverse event. Adverse events led to the withdrawal of one azithromycin group patient (abdominal pain) and

8 78 B. O'Doberty Table III. Summary of adverse events related or possibly related to treatment Body system/ adverse event Gastrointestinal abdominal pain constipation diarrhoea dyspepsia flatulence nausea vomiting Central nervous system Dermatological Eye, ear, nose, throat Genitourinary Respiratory system Other Total number of adverse events Total number of patients with adverse events Number (%) azithromycin (n = 267) 6 (2.2%) 1 (.4%) 9 (3.4%) 3 (1.1%) 1 (.4%) 9 (3.4%) 2 (.7%) 2 (.8%) 1 (.4%) 4 (1.4%) (1.9%) of events cefaclor (n = 263) 6 (2.3%) 1 (.4%) 1 (3.8%) 1 (.4%) 3 (1.1%) 3 (1.1%) 3 (1.1%) 1 (.4%) 7 (2.7%) (9.9%) five cefaclor-treated patients (nausea, genital candidosis, skin rash, diarrhoea, rhinitis) from study treatment. A categorical analysis of the data showed that the differences between treatment groups in the proportions of patients with adverse events, withdrawn from the study and with severe events were not statistically significant. Serious adverse events occurred in one patient in each treatment group. An azithromycin patient suffered a fatal myocardial infarction 5 days after completing study treatment, and a cefaclor patient was found to have myelogenous leukaemia on day 6. Neither of these events was considered related to study drug treatment. Changes in laboratory variables possibly related to treatment were recorded in 4% of azithromycin patients and 3% of cefaclor patients; none of these patients required treatment or further investigation. Discussion This study has demonstrated that a 3-day regimen of azithromycin, given as a once-daily 5 mg dose, is as effective and well tolerated as a 1-day course of cefaclor 25 mg administered three times daily in the treatment of patients with acute otitis media, pharyngitis/tonsillitis, or sinusitis. There was no significant difference between the treatments in terms of clinical response at the end of treatment or, where this was evaluable, in the eradication of the baseline pathogen. These results were consistent with previous studies demonstrating the efficacy of a three-day azithromycin regimen in patients with URTIs. In a non-comparative study a satisfactory clinical response was obtained in 87% of patients who received azithromycin 5 mg once daily for 3 days and the bacterial eradication rate was 83% (Soliman & Said, 1992). In a comparative study, the same 3-day azithromycin 5 mg regimen produced a satisfactory clinical response rate of 95%, which was comparable to a rate of 96% obtained with a ten-day

9 URTI treatment: azithromycin vs cefaclor 79 course of clarithromycin 25 mg twice daily (Muller, 1993). In addition, a number of paediatric studies with azithromycin once daily for 3 days at 1 mg/kg (maximum dose 5 mg) have produced clinical response rates of 93-98% for a variety of upper respiratory tract infections, including streptococcal pharyngitis. These results have been comparable to those achieved with 1-day courses of co-amoxiclav three times daily, amoxycillin three times daily, penicillin V four times daily, or erythromycin three times daily (Daniel, 1993; Hamill, 1993; Mohs et al., 1993; Schaad, 1993; Weippl, 1993). With some antibacterials used in the treatment of UTRIs drug interactions with the antispasmodics, theophylline and aminophylline, and with terfenadine, have been reported (Iliopoulou et al., 1982; Paulsen et al., 1987; Mathews et al., 1991). In the current study, three azithromycin-treated patients received theophylline and one terfenadine, and two cefaclor group patients received theophylline and one aminophylline. There was no evidence of drug interaction in either treatment group. Skin rashes are a known side-effect of cephalosporin treatment (Royal Pharmaceutical Society of Great Britain, 1993). In the present study, although two patients treated with cefaclor developed skin rashes and one experienced pruritus, no such adverse events were recorded for any patients who received azithromycin. It has been recognized, for some years, that both adult (Gatley, 1968) and paediatric patients (Bergman & Werner, 1963) comply poorly with anti-infective regimens that have multiple daily dosing and are longer than a week. There are numerous reasons for non-compliance, but the duration and frequency of dosing are among the most important (Greenberg, 1984; Cockburn et al., 1987). In clinical trials, selection and monitoring of patients reduces non-compliance, but in the general clinical setting the risk of poor compliance is always present. Poor compliance is likely to lead to an unsatisfactory outcome. This was demonstrated by Colcher & Bass (1972), who showed a positive correlation between non-compliance and relapse during the treatment of streptococcal pharyngitis with penicillin. Thus, an anti-infective agent with a simple dosing regimen, preferably once daily and a short duration of treatment should improve patient compliance and ultimately clinical outcome. The current study, in common with previous ones, has demonstrated that a 3-day, once-daily regimen of azithromycin is as effective as 1-day, multiple-daily dose regimens of other antibacterials. In clinical use, therefore, azithromycin may be more effective than antibacterials that require longer treatment regimens as patients will be more likely to complete the course of treatment. In conclusion, this study has demonstrated that azithromycin given as a once-daily 5 mg dose for 3 days is as effective and as well tolerated as cefaclor 25 mg given three times daily for 1 days for the treatment of adult patients with acute otitis media, pharyngitis/tonsillitis, or sinusitis. References Anderson, G., Esmonde, T. S., Coles, S., Macklin, J. & Carnegie, C. (1991). A comparative safety and efficacy study of clarithromycin and erythromycin stearate in community-acquired pneumonia. Journal of Antimicrobial Chemotherapy 27, Suppl. A, Aronoff, S. C, Laurent, C. & Jacobs, M. R. (1987). In-vitro activity of erythromycin, eroxithromycin and CP against common paediatric pathogens. Journal of Antimicrobial Chemotherapy 19, Bauer, A. W., Kirby W. M. M., Sherris, J. C. & Turck, M. (1966). Antibiotic susceptibility testing by a standardized single disk method. American Journal of Clinical Pathology 45,

10 8 B. O'Doherty Bergman, A. B. & Werner, R. J. (1963). Failure of children to receive penicillin by mouth. New England Journal of Medicine 268, Bright, G. M, Nagel, A. A., Bordner, J., Desai, K. A., Dibrino, J. N., Nowakowska, J. et al. (1988). Synthesis, in vitro and in vivo activity of novel 9-deoxo-9a-AZA-9a-homoerythromycin A derivatives: a new class of macrolide antibiotics, the a2alides. Journal of Antibiotics 41, 1O29^»7. Carbon, C. (1988). Cefaclor therapy for specific upper respiratory tract infections: pharyngitis, purulent rhinitis, laryngotracheitis. Clinical Therapeutics 11, Suppl. A, Cockburn, J., Gibberd, R. W., Reid, A. L. & Sanson-Fisher, R. W. (1987). Determinants of non-compliance with short-term antibiotic regimens. British Medical Journal 295, Cohen, R., de La Rocque, F., Boucherat, M., Lecompte, M. D., Bouhanna, A., Wollner, A. et al. (1991). Etude cefaclor versus penicilline V dans le angines streptococciques de l'enfant. Annales de Pediatrie 38, Colcher, I. S. & Bass, J. W. (1972). Penicillin treatment of streptococcal pharyngitis. A comparison of schedules and the role of specific counselling. Journal of the American Medical Association 222, Daniel, R. R. (1993). Comparison of azithromycin and co-amoxiclav in the treatment of otitis media in children. Journal of Antimicrobial Chemotherapy 31, Suppl. E, Dunkin, K. T., Jones, S. & Howard, A. J. (1988). The in-vitro activity of CP-62,993 against Haemophilus infiuenzae, Branhamella cattarhalis, staphylococci and streptococci. Journal of Antimicrobial Chemotherapy 21, Foulds, G., Chan, K. H., Johnson, J. T., Shepard, R. M. & Johnson, R. B. (1991). Concentrations of azithromycin in human tonsillar tissue. European Journal of Clinical Microbiology and Infectious Diseases 1, Foulds, G. & Johnson, R. B. (1993). Selection of dose regimens of azithromycin. Journal of Antimicrobial Chemotherapy 31, Suppl. E, Gatley, M. S. (1968). To be taken as directed. Journal of the Roval College of General Practitioners 16, Girard, A. E., Girard, D., English, A. R., Gootz, T. D., Cimochowski, C. R., Faiella, J. A. et al. (1987). Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrobial Agents and Chemotherapy 31, Greenberg, R. N. (1984). Overview of patient compliance with medication dosing: a literature review. Clinical Therapeutics 6, Hamill, J. (1993). Multicentre evaluation of azithromycin and penicillin V in the treatment of acute streptococcal pharyngitis and tonsillitis in children. Journal of Antimicrobial Chemotherapy 31, Suppl. E, Hardy, D. J., Hensey, D. M., Beyer, J. M., Vojtko, C, McDonald, E. J. & Fernandes, P. B. (1988). Comparative in vitro activities of new 14-, 15-, and 16-membered macrolides. Antimicrobial Agents and Chemotherapy 32, Iliopoulou, A., Aldhous, M. E., Johnston, A. & Turner, P. (1982). Pharmacokinetic interaction between theophylline and erythromycin. British Journal of Clinical Pharmacology 14, Mathews, D. R., McNutt, B., Oberholm, R., Flicker, M. & McBride, G. (1991). Torsades de pointes occurring in association with terfenadine use. Journal of the American Medical Association 266, McLinn, S. E. (1988). Cefaclor: a decade of experience in acute otitis media. Clinical Therapeutics 11, Suppl. A, Mohs, E., Rodriguez-Solares, A., Rivas, E. & El Hoshy, Z. (1993). A comparative study of azithromycin and amoxycillin in paediatric patients with acute otitis media. Journal of Antimicrobial Chemotherapy 31, Suppl. E, Muller, O. (1993). Comparison of azithromycin versus clarithromycin in the treatment of patients with upper respiratory tract infections. Journal of Antimicrobial Chemotherapy 31, Suppl. E, Nelson, J. D. (1988). Chronic suppurative otitis media. Pediatrie Infectious Diseases 7, Paulsen, O., Hoglund, P., Nilsson, L. G. & Bengtsson, H. I. (1987). The interaction of erythromycin and theophylline. European Journal of Clinical Pharmacology 32,

11 URTI treatment: azithromyein vs cefaclor 81 Pechere, J.-C. (1993. The use of macrolides in respiratory tract infections. International Journal of Antimicrobial Agents 3, S Pilot, M. A. & Qin, X. Y. (1988). Macrolides and gastrointestinal motility. Journal of Antimicrobial Chemotherapy 22, Suppl. B, Retsema, J., Girard, A., Schelkly, W., Manousos, M., Anderson, M., Bright, G. et al. (1987). Spectrum and mode of action of azithromyein (CP-62,993), a new 15-membered-ring macrolide with improved potency against Gram-negative organisms. Antimicrobial Agents and Chemotherapy 31, Royal Pharmaceutical Society of Great Britain. (1993). Martindale, the Extra Pharmacopeia, 3th edn (Reynolds, E. F., Ed.), pp The Pharmaceutical Press, London. Schaad, U. B. (1993). Multicentre evaluation of azithromyein in comparison with co-amoxiclav for the treatment of acute otitis media in children. Journal of Antimicrobial Chemotherapy 31, Suppl. E, Soliman, H. & Said, A. (1992). Oral azithromyein capsules, a new azalide in upper respiratory tract infections. Journal of the Egyptian Medical Association 75, Stillerman, M. (1986). Comparison of oral cephalosporins with penicillin therapy for group A streptococcal pharyngitis. Pediatric Infectious Diseases 5, Waldvogel, F. A. (1988). Summary of cefaclor: a decade of experience. Clinical Therapeutics 11, Suppl A, Weippl, G. (1993). Multicentre comparison of azithromyein versus erythromycin in the treatment of paediatric pharyngitis or tonsillitis caused by group A streptococci. Journal of Antimicrobial Chemotherapy 31, Suppl. E,