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clavulanate in the treatment of acute otitis media in pediatric patients
CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 9, SEPTEMBER 1994
COMPARATIVE SAFETY AND EFFICACY OF CLARITHROMYCIN VERSUS AMOXICILLIN/CLAVULANATE IN THE TREATMENT OF ACUTE OTITIS MEDIA IN PEDIATRIC PATIENTS J. M. McCARTY, 1 N. SIEPMAN, 2 A N D J. C. CRAFT 2
]California Medical Research Group, Fresno, California, and 2Abbott Laboratories, Abbott Park, Illinois
ABSTRACT
A pooled analysis of three randomized trials comparing suspension formulations of clarithromycin (7.5 mg/kg/dose twice daily; maximum dose, 500 mg) with amoxicillin/clavulanate (14 mg/kg/dose of amoxicillin component three times daily; maximum dose, 500 mg) in the treatment of acute otitis media in pediatric patients was performed. A total of 221 patients were treated with clarithromycin and 244 with amoxicillin/clavulanate. For evaluable patients, a successful outcome (clinical cure or improvement) was noted for 162 (92%) of 177 patients in the clarithromycin group and 187 (94%) of 199 patients in the amoxicillin/clavulanate group. Fifty-two (24%) patients in the clarithromycin group and 83 (34%) in the amoxicillin/clavulanate group reported adverse events (P = 0.014), the majority of which were mild or moderate in severity. Most adverse events in both groups were gastroin-
testinal complaints, which occurred in 36 (16%) of 221 clarithromycin patients and 74 (30%) of 244 amoxicillin/clavulanate patients (P < 0.001). The new macrolide clarithromycin appears to be as effective as and better tolerated than amoxicillin/clavulanate in the treatment of acute otitis media in pediatric patients. INTRODUCTION
Erythromycin and other macrolides are useful in treating respiratory tract infections caused by Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR), Moraxella catarrhalis, Streptococcus pyogenes, Streptococcus pneumoniae, and Staphylococcus aureus. 1"2However, these agents are considered to be generally unsuitable as monotherapy for acute otitis media in pediatric patients owing to their marginal activity against Haemophilus influenzae. The development of clarithromycin, a new macrolide, may offer an improved alternative to currently available macrolides. Clarithromycin has been demonstrated to have superior pharmacokinetic and adverse event profiles compared with those of erythromycin.3-6 Address correspondence to: J. M. McCarty, MD, California Medical Research Group, 3636 North 1st Street, Suite 133, Fresno, CA 93726. Received for publication on October26, 1993. Printed in the U.S.A. Reproduction in whole or part is not permitted. 1016
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In children, mean peak plasma concentrations after single and multiple (every 12 hours) 7.5-mg/kg doses of clarithromycin were 3.6 and 4.6 mg/L (clarithromycin) and 1.2 and 1.6 mg/L (active 14-OH metabolite), respectively. Food did not adversely affect clarithromycin bioavailability7 Concentrations of clarithromycin in respiratory tract tissues and secretions are nearly tenfold greater than those found in plasma, s-l° In pediatric patients, clarithromycin and its active 14-OH metabolite concentrate in middle ear effusion as well. At steady state, the mean +- SD middle ear effusion:serum concentration ratios for clarithromycin and the 14-OH metabolite were 2.48 +- 3.57 and 1.73 +- 1.40, respectively. 11 The in vitro spectrum of activity of clarithromycin is similar to that of erythromycin, with equal or greater activity against most macrolidesensitive o r g a n i s m s ) 2-16 There also is greater in vivo activity against H influenzae owing to an active metabolite, 14(R)-OH-clarithromycin, produced in vivo that has an additive or synergistic effect with the parent compound) 6'17 In therapeutically relevant ratios achieved in serum and tissues, the metabolite and parent compound together yield a minimum inhibitory concentration (MIC) that is 1-2 log2 dilution more potent than the parent compound alone. The improved pharmacokinetic and spectrum of activity profiles of clarithromycin suggest that this new agent m a y be useful in treating a variety of respiratory tract infections. In respiratory tract infection studies published to date, 17-~° clarithromycin has been shown to be effective and well tolerated. The purpose of this paper is to present the pooled results of three randomized, comparative trials of clarithromycin versus amoxicillin/ clavulanate in the treatment of acute otitis media in pediatric patients. PATIENTS AND METHODS
Outpatients (ages 1 to 12 years in two studies and 0.5 to 12 years in one study) with acute otitis media were enrolled in these randomized, multicenter trials. Two studies were blinded and the other was open. The diagnosis was based on clinical evidence, including the presence of at least one of the following: otalgia, irritability, tugging or rubbing of the ear, vomiting or diarrhea, fever, acute hearing loss, or upper respiratory tract infection; in association with hyperemia, decreased mobility or bulging of the tympanic membrane, loss of tympanic membrane landmarks, or acute otorrhea not caused by external otitis. Patients were to be in otherwise good health and female patients were to be at no risk of pregnancy. Patients were not eligible if they had a history of hypersensitivity to macrolide or beta-lactam antimicrobials, had been treated with a systemic antimicrobial within 3 days (two studies) or 7 days (one study) before the start of the study, had been treated with a 1017
CLARITHROMYCINVERSUS AMOXICILLIN/CLAVULANATE
topical (aural) antimicrobial for the current infection, or had been treated with a long-acting injectable antimicrobial within 4 weeks before study drug administration. In addition, patients were not eligible if there was evidence of significant renal or hepatic impairment (or clinically significant elevations in serum creatinine, transaminases, or bilirubin), chronic suppurative otitis media, or a perforated tympanum. Theophylline and carbamazepine cotherapy was permitted if serum concentrations were routinely monitored. Additional exclusion criteria for one study included a history of acute otitis media within 28 days of study enrollment; evidence of a physiologic, anatomic, or immunologic defect that would interfere with infection resolution; presence of any condition requiring treatment with a systemic or nasal decongestant during the study; concomitant probenecid or allopurinol therapy; or evidence of concomitant mononucleosis. Written informed consent, as approved by local institutional review boards, was granted by each patient's surrogate before study participation. Eligible patients were randomly assigned within each study by predetermined numerical sequence to receive either clarithromycin 7.5 rag/ kg/dose (maximum dose, 500 mg) every 12 hours or amoxicillin/ clavulanate 14 mg/kg/dose for the amoxicillin component (maximum dose, 500 mg) every 8 hours. Both drugs were administered as suspension formulations for 10 days. During the initial eligibility visit, we obtained a medical history and performed a physical examination, tympanometry (if possible), and clinical laboratory tests. An on-therapy visit (visit 2) was arranged if clinically indicated (two studies) or was mandatory (one study). At this visit, clinical signs and symptoms were evaluated, tympanometry was performed if possible, and adverse events and compliance with study drug therapy were assessed. Patients were requested to return within 48 hours posttreatment (visit 3). At this visit, clinical signs and symptoms were evaluated, a physical examination was performed, tympanometry was performed if possible, clinical laboratory tests were repeated, and adverse events and compliance with study drug therapy were assessed. A second posttreatment visit (visit 4) occurred 15 to 28 days after the final study dose was administered for any patient assigned a clinical response of improvement at visit 3 and for any patient who had a recurrence or worsening of clinical signs and symptoms during the posttreatment follow-up period. At this visit, clinical signs and symptoms and adverse events were assessed and tympanometry was performed if possible. To be eligible for inclusion in the efficacy analysis, the patients had to meet the following criteria: (1) the clinical diagnosis of acute otitis media was sufficiently supported by clinical signs and symptoms before treatment; (2) clinical evaluations were performed according to the visit time frames described previously; (3) the study drug was taken for at least 3 full days and for patients completing the study, at least 70% of the scheduled 1018
J.M. McCARTYET AL.
doses were taken; (4) no other antimicrobial was administered concomitantly or before the final posttreatment study visit; and (5) no potentially effective therapeutic procedure (myringotomy, tympanocentesis, grommet insertion) was performed concomitantly or before the final posttreatment study visit. Clinical response was assessed as cure (pretreatment signs and symptoms resolved), improvement (pretreatment signs and symptoms improved but unresolved), failure (pretreatment signs and symptoms unimproved or worsened), indeterminate, relapse (pretreatment signs and symptoms improved during treatment and worsened or recurred within 4 days after treatment), and recurrence (pretreatment signs and symptoms improved within 4 days posttreatment and worsened or recurred more than 4 days posttreatment).
Statistical Analysis The sample size of this analysis (177 evaluable patients in the clarithromycin group and 199 evaluable patients in the amoxicillin/ clavulanate group) allowed the detection of differences of 15% using a two-tailed hypothesis test at a significance level of 0.05 and a power of 0.90, assuming that the superior of the two treatment groups had a 90% clinical success rate. The two treatment groups were compared by using Fisher's exact test (two-tailed) and one-way analysis of variance for demographic and baseline clinical characteristics. Clinical response rates were compared between treatment groups using Fisher's exact test (two-tailed). In addition, changes from pretreatment to posttreatment in each clinical sign or symptom were summarized by treatment group. Adverse events were categorized using the COSTART system31 and were summarized by treatment group and compared using Fisher's exact test (two-tailed). All statistical evaluations were performed using the Statistical Analysis System (SAS), version 6.07 (SAS Institute Inc., Cary, North Carolina). Significance was assessed at the 5% level. RESULTS
A total of 465 patients were enrolled in the three comparative trials; 221 were t r e a t e d w i t h c l a r i t h r o m y c i n and 244 received amoxicillin/ clavulanate. One hundred seventy-seven (80%) patients in the clarithromycin group and 199 (82%) of those in the amoxicillin/clavulanate group were evaluable for clinical efficacy. Table I lists the primary reasons for exclusion from the efficacy analysis. Statistical comparison between treatment groups (clinically evaluable patients) revealed no significant differences in demographic or clinical 1019
CLARITHROMYCIN VERSUS AMOXICILLIN/CLAVULANATE
Table I. Primary reasons for exclusion from the efficacy analysis. No. of Patients Clarithromycin
Amoxicillin/ Clavulanate
15 10 3 7 3 1 3 1 1 0 0 0
11 9 10 3 2 4 1 2 0 1 1 1
Less than minimum therapy Study blind broken Mistiming of posttreatment examination No follow-up examination performed Concurrent antimicrobials Lost to follow-up Indeterminate chnical response No posttreatment examination performed Received wrong study drug Mistiming of follow-up examination Therapeutic procedures Received less than 70% of medication
characteristics (Table II). Patient ages ranged from 6 months to 12 years. The majority of patients were white (89%), and the female/male sex ratio was 214/162. The patients weighed between 6 and 60 kg. The proportions of patients with individual pretreatment signs or symptoms were similar for the evaluable patients in the clarithromycin
Table II. Demographic and clinical characteristics of evaluable patients. No. of Patients (%)
Age (yr) Mean +- SD Range Sex Male Female Weight (kg) Mean _+ SD Range No. of OM episodes within past 12 months Mean _+ SD Range Infection status Mild Moderate Severe Overall clinical condition Fair Poor
Clarithromycin (N = 177)
Amoxicillin/Clavulanate (N = 199)
4.2 -+ 3.1 0-12
4.2 _+ 32 0-12
98 79
116 83
18.0 _+ 9,5 6-56
18.2 _+ 9.5 7-60
2.3 _+ 1.6 1-9
2.4 _+ 1.6 1-12
30 I~771
31 16~I
119 28 (16)
133 35 (18)
30 1 (1)
34 17 2 (1)
OM = otitis media.
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and amoxicillin/clavulanate groups. The clarithromycin and amoxicillin/ clavulanate groups also were comparable with regard to frequencies of otalgia: mild (25% and 24% of patients, respectively), moderate (34% and 31%), and severe (18% and 22%); and tympanic hyperemia: mild (26% and 28%), moderate (50% and 48%), and severe (21% and 22%). The percentages of febrile (>38.0°C) patients were 38% for the clarithromycin group and 42% for the amoxicillin/clavulanate group. Tympanic bulging was present in 71% and 65% of the clarithromycin and amoxicillin/clavulanate patients, respectively. Tympanic mobility was abnormal in 91% and 92% of the clarithromycin and amoxicillin/clavulanate patients, respectively. Tympanic landmarks were partially or fully obscured in 90% and 91% of the clarithromycin and amoxicillin/clavulanate patients, respectively. Patients were comparable with regard to the frequencies of mild, moderate, or severe irritability; vomiting; diarrhea; and concurrent upper respiratory tract infection. One hundred fifty-one (85%) of 177 clarithromycin patients were considered clinically cured at the posttreatment visit and an additional 11 patients were considered clinically improved. Thus a clinically successful outcome was noted in 162 (92%) clarithromycin patients, with the remaining 15 (89%) patients being clinical failures or relapses. In the amoxicillin/ clavulanate group, 178 (89%) of 199 patients were considered clinical cures and an additional 9 (5) patients were considered clinically improved. A clinically successful outcome was noted in 187 (94%) of 199 amoxicillin/ clavulanate patients, with the remaining 12 (6%) patients being clinical failures or relapses. The differences between treatment groups were not statistically significant. Clinical recurrences occurred in 23 (12%) patients treated with clarithromycin and 32 (16%) of those treated with amoxicillin/ clavulanate during the posttreatment follow-up period. Significant improvements were noted for all signs and symptoms of acute otitis media in both treatment groups at the posttreatment visit (Table III). There were no significant differences between the two treatment groups in resolution or improvement rates in individual signs and symptoms. Two hundred seven patients had a pretreatment tympanogram performed o n a t least one ear. Ninety-two (92%) of 100 clarithromycin patients and 103 (96%) of 107 amoxicillin/clavulanate patients had an abnormal pretreatment tympanogram. The pretreatment abnormalities were resolved in 34% of the clarithromycin patients and 46% of the amoxicillin/clavulanate patients at the posttreatment visit. One patient in the amoxicillin]clavulanate group who had a normal pretreatment tympanogram had an abnormal tympanogram after treatment. All patients who took at least one dose of the study drug were included in the safety analysis. Adverse events not due to concurrent conditions
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CLARITHROMYCIN VERSUS AMOXICILLIN/CLAVULANATE
Table III. Clinical t r e a t m e n t outcomes for signs or symptoms.
No. of Patients (%) Sign or Symptom
Fever Resolution Otalgia Resolution Resolution or improvement Tympanic hyperemia Resolution Resolution or improvement Tympanic bulging Resolution Tympanic mobility Resolution Tympanic landmarks Resolution Resolution or improvement Acute otorrhea Resolution Irritability Resolution or improvement Vomiting Resolution Resolution or improvement Diarrhea Resolution Resolution or improvement Upper respiratory tract infection Resolution Resolution or improvement
Clarithromycin
Amoxicillin/Clavulanate
60/66 (91)
74/79 (94)
127/135 (94) 131/135 (97)
143/153 I~l 146/153
125/173 (72) 155/173 (90)
148/196/~l 183/196
112/126 (89)
117/130 (90)
88/159 (55)
112/182 (62)
104/160 (65) 127/160 (79)
132/181 /73/ 157/181
7/7 (100)
10/10 (100)
110/117 (94) 15/15 (100) 15/15 (100)
126/137 11/11 (100) 11/11 (100)
8/11 };~/ 8/11
5/8 }~/ 6/8
102/134/~6/ 113/134
130/163/~0/ 145/163
Assessments conducted within 0-4 days posttreatment (except for clinical failures). Data shown are for those patients with the sign or symptom present pretreatment and evaluated posttreatment.
were observed in 52 (24%) of the 221 clarithromycin patients and 83 (34%) of the 244 amoxicillin/clavulanate patients (P = 0.014) (Table IV). The majority of adverse events were mild to moderate in severity and gastrointestinal in nature. Thirty-six (16%) patients in the clarithromycin group and 74 (30%) in the amoxicillin/clavulanate group reported gastrointestinal events (P < 0.001), with diarrhea and vomiting as the chief complaint in both treatment groups. Diarrhea occurred in 9% of the patients treated with clarithromycin and 24% of those receiving amoxicillin/clavulanate (P < 0.001). Vomiting occurred in 5% and 7% of the clarithromycin and amoxicillin/clavulanate patients, respectively (P = 0.339). Severe adverse events were reported in none of the clarithromycin patients and in five of the amoxicillin/clavulanate patients (three reports of diarrhea and one each of vomiting and abdominal pain). Treatment was prematurely discontinued because of adverse events in five (2%) clarithromycin patients (gastrointestinal events in four patients and rash in one) and in 14 (6%)
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Table IV. Adverse events. No. of Patients (%) COSTART Term* Body as a whole Digestive system Gastrointestinal Diarrhea Other digestive Metabolic/nutritional Nervous system Respiratory system Skin and appendages Special senses Hemic/lymphatic Urogenital Overall
Clarithromycin (n = 221) 36 36
I1" )1
Amoxicillin/Clavulanate (n = 244) 7 (2.9) 75 (30.7)174 (30.3)1-
58 1~!88)12
1
1 (0[51 0 0 52 (23,5):~
1
5 1(014) 0 0 83 (34.0)~
* Body system classification via COSTARTmethodology21 Patients with more than one event within a body system were counted only once in the total for that system; patients with events in more than one body system were counted only once in the overall total. 1 P < 0.01. ~ P < 0.05.
amoxicillin/clavulanate patients (gastrointestinal events in all patients) (P = 0.064). No significant laboratory abnormalities occurred during the studies. DISCUSSION
Acute otitis media is a common illness in infants and children and occurs in 83% of individuals during the first three years of life. 32 Bacterial pathogens can be isolated in as m a n y as 90% of patients and most commonly include S pneumoniae, H influenzae, and M catarrhalis. 33 Beta-lactamaseproducing organisms are increasing in frequency and make up as m a n y as one third of the pathogens, raising concerns about the empiric use of amoxicillin as therapy. ~4 Because amoxicillin/clavulanate has been widely used to treat acute otitis media, comparing the efficacy of clarithromycin to this agent is a reasonable gauge of clarithromycin's potential utility. The data from this analysis of three comparative clinical trials demonstrated t h a t clarithromycin was very effective and safer than amoxicillin/clavulanate in the t r e a t m e n t of acute otitis media in children. The two t r e a t m e n t groups were similar with regard to sex, race, age, weight, number of previous otitis episodes, infection status, and overall clinical condition. A successful clinical outcome occurred in 92% of the clarithromycin' patients and 94% of the amoxicillin/clavulanate patients. A clinical recurrence occurred in 14% of those treated with clarithromycin and 17% of those receiving amoxicillin/clavulanate; these rates were similar to those seen in other otitis media antibiotic trials. 34-4° 1023
CLARITHROMYCINVERSUSAMOXICILLIN/CLAVULANATE
Both drugs produced similar rates of adverse events, with the exception of gastrointestinal events, which occurred in 30.3% of the patients receiving amoxicillin]clavulanate and 16.3% of those receiving clarithromycin. High rates of diarrhea have been noted previously with both amoxicillin/clavulanate and cefixime.34-36'39'4° For the most part, adverse events associated with clarithromycin and amoxicillin/clavulanate in the present trials were mild or moderate in severity. In conclusion, clarithromycin is as effective as and better tolerated than amoxicillin/clavulanate in the treatment of acute otitis media in children. Furthermore, clarithromycin offers a potential advantage over amoxicillin/clavulanate with its twice-daily dosing regimen. These advantages, in conjunction with clarithromycin's broad activity against most pathogens that cause acute otitis media, may be most important clinically when empiric antimicrobial therapy is routinely employed. References: 1. Wilson WR, Cockerill FRIII. Tetracyclines, chloramphenicol, erythromycin, and clindamycin. Mayo Clin Proc 1987; 62:906-915. 2. Reynolds HY. Chronic bronchitis and acute infectious exacerbations. In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases. 3rd ed. New York: Churchill Livingstone, 1990:531-535. 3. Hardy DJ, Guay DRP, Jones RN. Clarithromycin, a unique macrolide. A pharmacokinetic, microbiological, and clinical overview. Diagn Microbiol Infect Dis 1992; 15:39-53. 4. Guay DRP. Pharmacokinetics of new macrolides. Infect Med 1992; 9(Suppl A):31-38. 5. Periti P, Mazzei T, Mini E, Novelli A. Clinical pharmacokinetic properties of the macrolide antibiotics. Clin Pharmacokin 1989; 16:193-214, 261-282. 6. Guay DRP, Patterson DR, Seipman N, Craft JC. Overview of the tolerability profile of clarithromycin in preclinical and clinical trials. Drug Safety 1993; 8:350-364. 7. Gan VN, Chu S-Y, Kusmiesz HT, Craft JC. Pharmacokinetics of a clarithromycin suspension in infants and children. Antimicrob Agents Chemother 1992; 36:2478-2480. 8. Suwa T, Yoshida H, Yoshitomi S, Kamei K. Metabolism of TE-031 (A-56268), a new macrolide antibiotic, in rat, dog and man. (Abstract 414) Proceedings of the 26th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, September 28-October 1, 1986. 9. Goto J, Ikuta M, Yamasaki T, et al. Preclinical studies of TE-031 (A-56268), a macrolide, and clinical study on its application in respiratory tract infections. Chemotherapy 1988; 36(Suppl 3):737-747. 10. Fraschini F, Scaglione F, Pintucci G, et al. The diffusion of clarithromycin and roxithromycin into nasal mucosa, tonsil and lung in humans. J Antimicrob Chemother 1991; 27(Suppl A):61-65. 11. Guay DRP, Craft JC. Overview of the pharmacology of clarithromycin suspension in children and a comparison with that in adults. Pediatr Infect Dis J 1993;12(Suppl 3):5106-5111. 12. Jansson L, Kalin M. Comparative in vitro activity of A-56268 against respiratory tract pathogens. Eur J Clin Microbiol Infect Dis 1987; 6:494-496. 1024
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13. Benson CA, Segreti J, Beaudette FE, et at. In vitro activity of A-56268 (TE-031), a new macrolide, compared with that of erythromycin and clindamycin against selected grampositive and gram-negative organisms. A ntimicrob Agents Chemother 1987; 31:328 - 330. 14. Fernandes PB, Bailer R, Swanson R, et al. In vitro and in vivo evaluation of A-56268 (TE-031), a new macrolide. Antimicrob Agents Chemother 1986; 30:865-873. 15. Hardy DJ, Hensey DM, Beyer JM, et al. Comparative in vitro activities of 14-, 15-, and 16-membered macrolides. Antimicrob Agents Chemother 1988; 32:1710-1719. 16. Hardy DJ, Swanson RN, Rode RA, et al. Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin,its major metabolite in humans. Antimicrob Agents Chemother 1990; 34:1407-1413. 17. Fernandes PB, Hardy D, Bailer R, et al. Susceptibility testing of macrolide antibiotics against Haemophilus influenzae and correlation of in vitro results with in vivo efficacy in a mouse septicemia model. Antimicrob Agents Chemother 1987; 31:1243-1250. 18. Guay DRP, Craft JC. Comparative safety and efficacy of clarithromycin and ampicillin in the treatment of outpatients with acute bacterial exacerbation of chronic bronchitis. J Intern Med 1992; 231:295-301. 19. Fraschini F. Clinical efficacy and tolerance of two new macrolides, clarithromycin and josamycin, in the treatment of patients with acute exacerbation of chronic bronchitis. J Int Med Res 1990; 18:171-176. 20. Karma P, Pukander J, Penttila M, et al. The comparative efficacy and safety ofclarithromycin and amoxicillin in the treatment of outpatients with acute maxillary sinusitis. J Antimicrob Chemother 1991; 27(Suppl A):83-90. 21. Aldons PM. A comparison of clarithromycin with ampicitlin in the treatment of outpatients with acute bacterial exacerbation of chronic bronchitis. J Antimicrob Chemother 1991; 27(Suppl A):101-108. 22. Anderson G, Esmonde TS, Coles S, et al. A comparative safety and efficacy study of clarithromycin and erythromycin stearate in community-acquired pneumonia. J Antimicrob Chemother 1991; 27(Suppl A):117-124. 23. Bachand RT Jr. A comparative study of clarithromycin and penicillin VK in the treatment of outpatients with streptococcal pharyngitis. J Antimicrob Chemother 1991; 27(Suppl A):75-82. 24. Bachand RT Jr. Comparative study of clarithromycin and ampicillin in the treatment of patients with acute bacterial exacerbations of chronic bronchitis. J Antimicrob Chemother 1991; 27(Suppl A):91-100. 25. Scaglione F. Comparison of the clinical and bacteriological efficacy of clarithromycin and erythromycin in the treatment of streptococcal pharyngitis. Curr Med Res Opin 1990; 12:25-33. 26. Straneo G, Scarpazza G. Efficacy and safety of clarithromycin versus josamycin in the treatment of hospitalized patients with bacterial pneumonia. J Int Med Res 1990; 18: 164-170. 27. Marchi E. Comparative efficacy and tolerability of clarithromycin and amoxicillin in the treatment of outpatients with acute maxillary sinusitis. Curr Med Res Opin 1990; 12: 19-24. 28. Levenstein JH. Clarithromycin versus penicillin in the treatment of streptococcal pharyngitis. J Antimicrob Chemother 1991; 27(Suppl A):67-74. 1025
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29. Poirier R. Comparative study of clarithromycin and roxithromycin in the treatment of community-acquired pneumonia. J Antimicrob Chemother 1991; 27(Suppl A):109-116. 30. Guay DRP, Siepman N, Tanaka SK, et al. Comparative safety and efficacy of clarithromycin and 3 oral cephalosporins in the treatment of outpatients with bacterial bronchitis due to Haemophilus influenzae. Drug Invest 1993; 6:33-41. 31. Department of Health and Human Services. COSTART coding symbols for thesaurus of adverse reaction terms. Rockville, MD: Food and Drug Administration, 1990. 32. Teele DW, Klein JO, Rosner B, and the Greater Boston Otitis Media Study Group. Epidemiology of otitis media during the first seven years of life in children in greater Boston: A prospective, cohort study. J Infect Dis 1989; 160:83-94. 33. Del Beccaro MA, Mendelman PM, Inglis AF, et al. Bacteriology of acute otitis media: A new perspective. J Pediatr 1992; 120:81-84. 34. Mendelman PM, Del Beccaro MA, Mclinn SE, Todd WM. Cefpodoxime proxetil compared with amoxicillin-clavulanate for the treatment of otitis media. J Pediatr 1992; 121:459465. 35. Foshee WS. Loracarbef (LY163892) versus amoxicillin-clavulanate in the treatment of bacterial acute otitis media with effusion. J Pediatr 1992; 120:980-986. 36. Stutman HR, Arguedas AG. Comparison of cefprozil with other antibiotic regimens in the treatment of children with acute otitis media. Clin Infect Dis 1992; 14(Suppl 2):$204$208. 37. Odio CM, Kusmiesz H, Shelton S, Nelson JD. Comparative treatment of augmentin versus cefaclor for acute otitis media with effusion. Pediatrics 1985; 75:819-826. 38. Blumer JL, Bertino JS, Husak MP. Comparison of cefaclor and trimethoprimsulfamethoxazole in the treatment of acute otitis media. Pediatr Infect Dis J 1984; 3:2529. 39. Kenna MA, Bluestone CD, Fall P, et al. Cefixime vs. cefaclor in the treatment of acute otitis media in infants and children. Pediatr Infect Dis J 1987; 6:992-996. 40. Marchant CD, Shurin PA, Johnson CE, et al. A randomized controlled trial of amoxicillin plus clavulanate compared with cefaclor for treatment of acute otitis media. J Pediatr 1986; 109:891-896.
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COMPARATIVE SAFETY AND EFFICACY OF CLARITHROMYCIN VERSUS AMOXICILLIN/CLAVULANATE IN THE TREATMENT OF ACUTE OTITIS MEDIA IN PEDIATRIC PATIENTS J. M. McCARTY, 1 N. SIEPMAN, 2 A N D J. C. CRAFT 2
]California Medical Research Group, Fresno, California, and 2Abbott Laboratories, Abbott Park, Illinois
ABSTRACT
A pooled analysis of three randomized trials comparing suspension formulations of clarithromycin (7.5 mg/kg/dose twice daily; maximum dose, 500 mg) with amoxicillin/clavulanate (14 mg/kg/dose of amoxicillin component three times daily; maximum dose, 500 mg) in the treatment of acute otitis media in pediatric patients was performed. A total of 221 patients were treated with clarithromycin and 244 with amoxicillin/clavulanate. For evaluable patients, a successful outcome (clinical cure or improvement) was noted for 162 (92%) of 177 patients in the clarithromycin group and 187 (94%) of 199 patients in the amoxicillin/clavulanate group. Fifty-two (24%) patients in the clarithromycin group and 83 (34%) in the amoxicillin/clavulanate group reported adverse events (P = 0.014), the majority of which were mild or moderate in severity. Most adverse events in both groups were gastroin-
testinal complaints, which occurred in 36 (16%) of 221 clarithromycin patients and 74 (30%) of 244 amoxicillin/clavulanate patients (P < 0.001). The new macrolide clarithromycin appears to be as effective as and better tolerated than amoxicillin/clavulanate in the treatment of acute otitis media in pediatric patients. INTRODUCTION
Erythromycin and other macrolides are useful in treating respiratory tract infections caused by Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR), Moraxella catarrhalis, Streptococcus pyogenes, Streptococcus pneumoniae, and Staphylococcus aureus. 1"2However, these agents are considered to be generally unsuitable as monotherapy for acute otitis media in pediatric patients owing to their marginal activity against Haemophilus influenzae. The development of clarithromycin, a new macrolide, may offer an improved alternative to currently available macrolides. Clarithromycin has been demonstrated to have superior pharmacokinetic and adverse event profiles compared with those of erythromycin.3-6 Address correspondence to: J. M. McCarty, MD, California Medical Research Group, 3636 North 1st Street, Suite 133, Fresno, CA 93726. Received for publication on October26, 1993. Printed in the U.S.A. Reproduction in whole or part is not permitted. 1016
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J. M. McCARTYET AL.
In children, mean peak plasma concentrations after single and multiple (every 12 hours) 7.5-mg/kg doses of clarithromycin were 3.6 and 4.6 mg/L (clarithromycin) and 1.2 and 1.6 mg/L (active 14-OH metabolite), respectively. Food did not adversely affect clarithromycin bioavailability7 Concentrations of clarithromycin in respiratory tract tissues and secretions are nearly tenfold greater than those found in plasma, s-l° In pediatric patients, clarithromycin and its active 14-OH metabolite concentrate in middle ear effusion as well. At steady state, the mean +- SD middle ear effusion:serum concentration ratios for clarithromycin and the 14-OH metabolite were 2.48 +- 3.57 and 1.73 +- 1.40, respectively. 11 The in vitro spectrum of activity of clarithromycin is similar to that of erythromycin, with equal or greater activity against most macrolidesensitive o r g a n i s m s ) 2-16 There also is greater in vivo activity against H influenzae owing to an active metabolite, 14(R)-OH-clarithromycin, produced in vivo that has an additive or synergistic effect with the parent compound) 6'17 In therapeutically relevant ratios achieved in serum and tissues, the metabolite and parent compound together yield a minimum inhibitory concentration (MIC) that is 1-2 log2 dilution more potent than the parent compound alone. The improved pharmacokinetic and spectrum of activity profiles of clarithromycin suggest that this new agent m a y be useful in treating a variety of respiratory tract infections. In respiratory tract infection studies published to date, 17-~° clarithromycin has been shown to be effective and well tolerated. The purpose of this paper is to present the pooled results of three randomized, comparative trials of clarithromycin versus amoxicillin/ clavulanate in the treatment of acute otitis media in pediatric patients. PATIENTS AND METHODS
Outpatients (ages 1 to 12 years in two studies and 0.5 to 12 years in one study) with acute otitis media were enrolled in these randomized, multicenter trials. Two studies were blinded and the other was open. The diagnosis was based on clinical evidence, including the presence of at least one of the following: otalgia, irritability, tugging or rubbing of the ear, vomiting or diarrhea, fever, acute hearing loss, or upper respiratory tract infection; in association with hyperemia, decreased mobility or bulging of the tympanic membrane, loss of tympanic membrane landmarks, or acute otorrhea not caused by external otitis. Patients were to be in otherwise good health and female patients were to be at no risk of pregnancy. Patients were not eligible if they had a history of hypersensitivity to macrolide or beta-lactam antimicrobials, had been treated with a systemic antimicrobial within 3 days (two studies) or 7 days (one study) before the start of the study, had been treated with a 1017
CLARITHROMYCINVERSUS AMOXICILLIN/CLAVULANATE
topical (aural) antimicrobial for the current infection, or had been treated with a long-acting injectable antimicrobial within 4 weeks before study drug administration. In addition, patients were not eligible if there was evidence of significant renal or hepatic impairment (or clinically significant elevations in serum creatinine, transaminases, or bilirubin), chronic suppurative otitis media, or a perforated tympanum. Theophylline and carbamazepine cotherapy was permitted if serum concentrations were routinely monitored. Additional exclusion criteria for one study included a history of acute otitis media within 28 days of study enrollment; evidence of a physiologic, anatomic, or immunologic defect that would interfere with infection resolution; presence of any condition requiring treatment with a systemic or nasal decongestant during the study; concomitant probenecid or allopurinol therapy; or evidence of concomitant mononucleosis. Written informed consent, as approved by local institutional review boards, was granted by each patient's surrogate before study participation. Eligible patients were randomly assigned within each study by predetermined numerical sequence to receive either clarithromycin 7.5 rag/ kg/dose (maximum dose, 500 mg) every 12 hours or amoxicillin/ clavulanate 14 mg/kg/dose for the amoxicillin component (maximum dose, 500 mg) every 8 hours. Both drugs were administered as suspension formulations for 10 days. During the initial eligibility visit, we obtained a medical history and performed a physical examination, tympanometry (if possible), and clinical laboratory tests. An on-therapy visit (visit 2) was arranged if clinically indicated (two studies) or was mandatory (one study). At this visit, clinical signs and symptoms were evaluated, tympanometry was performed if possible, and adverse events and compliance with study drug therapy were assessed. Patients were requested to return within 48 hours posttreatment (visit 3). At this visit, clinical signs and symptoms were evaluated, a physical examination was performed, tympanometry was performed if possible, clinical laboratory tests were repeated, and adverse events and compliance with study drug therapy were assessed. A second posttreatment visit (visit 4) occurred 15 to 28 days after the final study dose was administered for any patient assigned a clinical response of improvement at visit 3 and for any patient who had a recurrence or worsening of clinical signs and symptoms during the posttreatment follow-up period. At this visit, clinical signs and symptoms and adverse events were assessed and tympanometry was performed if possible. To be eligible for inclusion in the efficacy analysis, the patients had to meet the following criteria: (1) the clinical diagnosis of acute otitis media was sufficiently supported by clinical signs and symptoms before treatment; (2) clinical evaluations were performed according to the visit time frames described previously; (3) the study drug was taken for at least 3 full days and for patients completing the study, at least 70% of the scheduled 1018
J.M. McCARTYET AL.
doses were taken; (4) no other antimicrobial was administered concomitantly or before the final posttreatment study visit; and (5) no potentially effective therapeutic procedure (myringotomy, tympanocentesis, grommet insertion) was performed concomitantly or before the final posttreatment study visit. Clinical response was assessed as cure (pretreatment signs and symptoms resolved), improvement (pretreatment signs and symptoms improved but unresolved), failure (pretreatment signs and symptoms unimproved or worsened), indeterminate, relapse (pretreatment signs and symptoms improved during treatment and worsened or recurred within 4 days after treatment), and recurrence (pretreatment signs and symptoms improved within 4 days posttreatment and worsened or recurred more than 4 days posttreatment).
Statistical Analysis The sample size of this analysis (177 evaluable patients in the clarithromycin group and 199 evaluable patients in the amoxicillin/ clavulanate group) allowed the detection of differences of 15% using a two-tailed hypothesis test at a significance level of 0.05 and a power of 0.90, assuming that the superior of the two treatment groups had a 90% clinical success rate. The two treatment groups were compared by using Fisher's exact test (two-tailed) and one-way analysis of variance for demographic and baseline clinical characteristics. Clinical response rates were compared between treatment groups using Fisher's exact test (two-tailed). In addition, changes from pretreatment to posttreatment in each clinical sign or symptom were summarized by treatment group. Adverse events were categorized using the COSTART system31 and were summarized by treatment group and compared using Fisher's exact test (two-tailed). All statistical evaluations were performed using the Statistical Analysis System (SAS), version 6.07 (SAS Institute Inc., Cary, North Carolina). Significance was assessed at the 5% level. RESULTS
A total of 465 patients were enrolled in the three comparative trials; 221 were t r e a t e d w i t h c l a r i t h r o m y c i n and 244 received amoxicillin/ clavulanate. One hundred seventy-seven (80%) patients in the clarithromycin group and 199 (82%) of those in the amoxicillin/clavulanate group were evaluable for clinical efficacy. Table I lists the primary reasons for exclusion from the efficacy analysis. Statistical comparison between treatment groups (clinically evaluable patients) revealed no significant differences in demographic or clinical 1019
CLARITHROMYCIN VERSUS AMOXICILLIN/CLAVULANATE
Table I. Primary reasons for exclusion from the efficacy analysis. No. of Patients Clarithromycin
Amoxicillin/ Clavulanate
15 10 3 7 3 1 3 1 1 0 0 0
11 9 10 3 2 4 1 2 0 1 1 1
Less than minimum therapy Study blind broken Mistiming of posttreatment examination No follow-up examination performed Concurrent antimicrobials Lost to follow-up Indeterminate chnical response No posttreatment examination performed Received wrong study drug Mistiming of follow-up examination Therapeutic procedures Received less than 70% of medication
characteristics (Table II). Patient ages ranged from 6 months to 12 years. The majority of patients were white (89%), and the female/male sex ratio was 214/162. The patients weighed between 6 and 60 kg. The proportions of patients with individual pretreatment signs or symptoms were similar for the evaluable patients in the clarithromycin
Table II. Demographic and clinical characteristics of evaluable patients. No. of Patients (%)
Age (yr) Mean +- SD Range Sex Male Female Weight (kg) Mean _+ SD Range No. of OM episodes within past 12 months Mean _+ SD Range Infection status Mild Moderate Severe Overall clinical condition Fair Poor
Clarithromycin (N = 177)
Amoxicillin/Clavulanate (N = 199)
4.2 -+ 3.1 0-12
4.2 _+ 32 0-12
98 79
116 83
18.0 _+ 9,5 6-56
18.2 _+ 9.5 7-60
2.3 _+ 1.6 1-9
2.4 _+ 1.6 1-12
30 I~771
31 16~I
119 28 (16)
133 35 (18)
30 1 (1)
34 17 2 (1)
OM = otitis media.
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J. M. McCARTY ET AL.
and amoxicillin/clavulanate groups. The clarithromycin and amoxicillin/ clavulanate groups also were comparable with regard to frequencies of otalgia: mild (25% and 24% of patients, respectively), moderate (34% and 31%), and severe (18% and 22%); and tympanic hyperemia: mild (26% and 28%), moderate (50% and 48%), and severe (21% and 22%). The percentages of febrile (>38.0°C) patients were 38% for the clarithromycin group and 42% for the amoxicillin/clavulanate group. Tympanic bulging was present in 71% and 65% of the clarithromycin and amoxicillin/clavulanate patients, respectively. Tympanic mobility was abnormal in 91% and 92% of the clarithromycin and amoxicillin/clavulanate patients, respectively. Tympanic landmarks were partially or fully obscured in 90% and 91% of the clarithromycin and amoxicillin/clavulanate patients, respectively. Patients were comparable with regard to the frequencies of mild, moderate, or severe irritability; vomiting; diarrhea; and concurrent upper respiratory tract infection. One hundred fifty-one (85%) of 177 clarithromycin patients were considered clinically cured at the posttreatment visit and an additional 11 patients were considered clinically improved. Thus a clinically successful outcome was noted in 162 (92%) clarithromycin patients, with the remaining 15 (89%) patients being clinical failures or relapses. In the amoxicillin/ clavulanate group, 178 (89%) of 199 patients were considered clinical cures and an additional 9 (5) patients were considered clinically improved. A clinically successful outcome was noted in 187 (94%) of 199 amoxicillin/ clavulanate patients, with the remaining 12 (6%) patients being clinical failures or relapses. The differences between treatment groups were not statistically significant. Clinical recurrences occurred in 23 (12%) patients treated with clarithromycin and 32 (16%) of those treated with amoxicillin/ clavulanate during the posttreatment follow-up period. Significant improvements were noted for all signs and symptoms of acute otitis media in both treatment groups at the posttreatment visit (Table III). There were no significant differences between the two treatment groups in resolution or improvement rates in individual signs and symptoms. Two hundred seven patients had a pretreatment tympanogram performed o n a t least one ear. Ninety-two (92%) of 100 clarithromycin patients and 103 (96%) of 107 amoxicillin/clavulanate patients had an abnormal pretreatment tympanogram. The pretreatment abnormalities were resolved in 34% of the clarithromycin patients and 46% of the amoxicillin/clavulanate patients at the posttreatment visit. One patient in the amoxicillin]clavulanate group who had a normal pretreatment tympanogram had an abnormal tympanogram after treatment. All patients who took at least one dose of the study drug were included in the safety analysis. Adverse events not due to concurrent conditions
1021
CLARITHROMYCIN VERSUS AMOXICILLIN/CLAVULANATE
Table III. Clinical t r e a t m e n t outcomes for signs or symptoms.
No. of Patients (%) Sign or Symptom
Fever Resolution Otalgia Resolution Resolution or improvement Tympanic hyperemia Resolution Resolution or improvement Tympanic bulging Resolution Tympanic mobility Resolution Tympanic landmarks Resolution Resolution or improvement Acute otorrhea Resolution Irritability Resolution or improvement Vomiting Resolution Resolution or improvement Diarrhea Resolution Resolution or improvement Upper respiratory tract infection Resolution Resolution or improvement
Clarithromycin
Amoxicillin/Clavulanate
60/66 (91)
74/79 (94)
127/135 (94) 131/135 (97)
143/153 I~l 146/153
125/173 (72) 155/173 (90)
148/196/~l 183/196
112/126 (89)
117/130 (90)
88/159 (55)
112/182 (62)
104/160 (65) 127/160 (79)
132/181 /73/ 157/181
7/7 (100)
10/10 (100)
110/117 (94) 15/15 (100) 15/15 (100)
126/137 11/11 (100) 11/11 (100)
8/11 };~/ 8/11
5/8 }~/ 6/8
102/134/~6/ 113/134
130/163/~0/ 145/163
Assessments conducted within 0-4 days posttreatment (except for clinical failures). Data shown are for those patients with the sign or symptom present pretreatment and evaluated posttreatment.
were observed in 52 (24%) of the 221 clarithromycin patients and 83 (34%) of the 244 amoxicillin/clavulanate patients (P = 0.014) (Table IV). The majority of adverse events were mild to moderate in severity and gastrointestinal in nature. Thirty-six (16%) patients in the clarithromycin group and 74 (30%) in the amoxicillin/clavulanate group reported gastrointestinal events (P < 0.001), with diarrhea and vomiting as the chief complaint in both treatment groups. Diarrhea occurred in 9% of the patients treated with clarithromycin and 24% of those receiving amoxicillin/clavulanate (P < 0.001). Vomiting occurred in 5% and 7% of the clarithromycin and amoxicillin/clavulanate patients, respectively (P = 0.339). Severe adverse events were reported in none of the clarithromycin patients and in five of the amoxicillin/clavulanate patients (three reports of diarrhea and one each of vomiting and abdominal pain). Treatment was prematurely discontinued because of adverse events in five (2%) clarithromycin patients (gastrointestinal events in four patients and rash in one) and in 14 (6%)
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J. M. McCARTY ET AL.
Table IV. Adverse events. No. of Patients (%) COSTART Term* Body as a whole Digestive system Gastrointestinal Diarrhea Other digestive Metabolic/nutritional Nervous system Respiratory system Skin and appendages Special senses Hemic/lymphatic Urogenital Overall
Clarithromycin (n = 221) 36 36
I1" )1
Amoxicillin/Clavulanate (n = 244) 7 (2.9) 75 (30.7)174 (30.3)1-
58 1~!88)12
1
1 (0[51 0 0 52 (23,5):~
1
5 1(014) 0 0 83 (34.0)~
* Body system classification via COSTARTmethodology21 Patients with more than one event within a body system were counted only once in the total for that system; patients with events in more than one body system were counted only once in the overall total. 1 P < 0.01. ~ P < 0.05.
amoxicillin/clavulanate patients (gastrointestinal events in all patients) (P = 0.064). No significant laboratory abnormalities occurred during the studies. DISCUSSION
Acute otitis media is a common illness in infants and children and occurs in 83% of individuals during the first three years of life. 32 Bacterial pathogens can be isolated in as m a n y as 90% of patients and most commonly include S pneumoniae, H influenzae, and M catarrhalis. 33 Beta-lactamaseproducing organisms are increasing in frequency and make up as m a n y as one third of the pathogens, raising concerns about the empiric use of amoxicillin as therapy. ~4 Because amoxicillin/clavulanate has been widely used to treat acute otitis media, comparing the efficacy of clarithromycin to this agent is a reasonable gauge of clarithromycin's potential utility. The data from this analysis of three comparative clinical trials demonstrated t h a t clarithromycin was very effective and safer than amoxicillin/clavulanate in the t r e a t m e n t of acute otitis media in children. The two t r e a t m e n t groups were similar with regard to sex, race, age, weight, number of previous otitis episodes, infection status, and overall clinical condition. A successful clinical outcome occurred in 92% of the clarithromycin' patients and 94% of the amoxicillin/clavulanate patients. A clinical recurrence occurred in 14% of those treated with clarithromycin and 17% of those receiving amoxicillin/clavulanate; these rates were similar to those seen in other otitis media antibiotic trials. 34-4° 1023
CLARITHROMYCINVERSUSAMOXICILLIN/CLAVULANATE
Both drugs produced similar rates of adverse events, with the exception of gastrointestinal events, which occurred in 30.3% of the patients receiving amoxicillin]clavulanate and 16.3% of those receiving clarithromycin. High rates of diarrhea have been noted previously with both amoxicillin/clavulanate and cefixime.34-36'39'4° For the most part, adverse events associated with clarithromycin and amoxicillin/clavulanate in the present trials were mild or moderate in severity. In conclusion, clarithromycin is as effective as and better tolerated than amoxicillin/clavulanate in the treatment of acute otitis media in children. Furthermore, clarithromycin offers a potential advantage over amoxicillin/clavulanate with its twice-daily dosing regimen. These advantages, in conjunction with clarithromycin's broad activity against most pathogens that cause acute otitis media, may be most important clinically when empiric antimicrobial therapy is routinely employed. References: 1. Wilson WR, Cockerill FRIII. Tetracyclines, chloramphenicol, erythromycin, and clindamycin. Mayo Clin Proc 1987; 62:906-915. 2. Reynolds HY. Chronic bronchitis and acute infectious exacerbations. In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases. 3rd ed. New York: Churchill Livingstone, 1990:531-535. 3. Hardy DJ, Guay DRP, Jones RN. Clarithromycin, a unique macrolide. A pharmacokinetic, microbiological, and clinical overview. Diagn Microbiol Infect Dis 1992; 15:39-53. 4. Guay DRP. Pharmacokinetics of new macrolides. Infect Med 1992; 9(Suppl A):31-38. 5. Periti P, Mazzei T, Mini E, Novelli A. Clinical pharmacokinetic properties of the macrolide antibiotics. Clin Pharmacokin 1989; 16:193-214, 261-282. 6. Guay DRP, Patterson DR, Seipman N, Craft JC. Overview of the tolerability profile of clarithromycin in preclinical and clinical trials. Drug Safety 1993; 8:350-364. 7. Gan VN, Chu S-Y, Kusmiesz HT, Craft JC. Pharmacokinetics of a clarithromycin suspension in infants and children. Antimicrob Agents Chemother 1992; 36:2478-2480. 8. Suwa T, Yoshida H, Yoshitomi S, Kamei K. Metabolism of TE-031 (A-56268), a new macrolide antibiotic, in rat, dog and man. (Abstract 414) Proceedings of the 26th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, September 28-October 1, 1986. 9. Goto J, Ikuta M, Yamasaki T, et al. Preclinical studies of TE-031 (A-56268), a macrolide, and clinical study on its application in respiratory tract infections. Chemotherapy 1988; 36(Suppl 3):737-747. 10. Fraschini F, Scaglione F, Pintucci G, et al. The diffusion of clarithromycin and roxithromycin into nasal mucosa, tonsil and lung in humans. J Antimicrob Chemother 1991; 27(Suppl A):61-65. 11. Guay DRP, Craft JC. Overview of the pharmacology of clarithromycin suspension in children and a comparison with that in adults. Pediatr Infect Dis J 1993;12(Suppl 3):5106-5111. 12. Jansson L, Kalin M. Comparative in vitro activity of A-56268 against respiratory tract pathogens. Eur J Clin Microbiol Infect Dis 1987; 6:494-496. 1024
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13. Benson CA, Segreti J, Beaudette FE, et at. In vitro activity of A-56268 (TE-031), a new macrolide, compared with that of erythromycin and clindamycin against selected grampositive and gram-negative organisms. A ntimicrob Agents Chemother 1987; 31:328 - 330. 14. Fernandes PB, Bailer R, Swanson R, et al. In vitro and in vivo evaluation of A-56268 (TE-031), a new macrolide. Antimicrob Agents Chemother 1986; 30:865-873. 15. Hardy DJ, Hensey DM, Beyer JM, et al. Comparative in vitro activities of 14-, 15-, and 16-membered macrolides. Antimicrob Agents Chemother 1988; 32:1710-1719. 16. Hardy DJ, Swanson RN, Rode RA, et al. Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin,its major metabolite in humans. Antimicrob Agents Chemother 1990; 34:1407-1413. 17. Fernandes PB, Hardy D, Bailer R, et al. Susceptibility testing of macrolide antibiotics against Haemophilus influenzae and correlation of in vitro results with in vivo efficacy in a mouse septicemia model. Antimicrob Agents Chemother 1987; 31:1243-1250. 18. Guay DRP, Craft JC. Comparative safety and efficacy of clarithromycin and ampicillin in the treatment of outpatients with acute bacterial exacerbation of chronic bronchitis. J Intern Med 1992; 231:295-301. 19. Fraschini F. Clinical efficacy and tolerance of two new macrolides, clarithromycin and josamycin, in the treatment of patients with acute exacerbation of chronic bronchitis. J Int Med Res 1990; 18:171-176. 20. Karma P, Pukander J, Penttila M, et al. The comparative efficacy and safety ofclarithromycin and amoxicillin in the treatment of outpatients with acute maxillary sinusitis. J Antimicrob Chemother 1991; 27(Suppl A):83-90. 21. Aldons PM. A comparison of clarithromycin with ampicitlin in the treatment of outpatients with acute bacterial exacerbation of chronic bronchitis. J Antimicrob Chemother 1991; 27(Suppl A):101-108. 22. Anderson G, Esmonde TS, Coles S, et al. A comparative safety and efficacy study of clarithromycin and erythromycin stearate in community-acquired pneumonia. J Antimicrob Chemother 1991; 27(Suppl A):117-124. 23. Bachand RT Jr. A comparative study of clarithromycin and penicillin VK in the treatment of outpatients with streptococcal pharyngitis. J Antimicrob Chemother 1991; 27(Suppl A):75-82. 24. Bachand RT Jr. Comparative study of clarithromycin and ampicillin in the treatment of patients with acute bacterial exacerbations of chronic bronchitis. J Antimicrob Chemother 1991; 27(Suppl A):91-100. 25. Scaglione F. Comparison of the clinical and bacteriological efficacy of clarithromycin and erythromycin in the treatment of streptococcal pharyngitis. Curr Med Res Opin 1990; 12:25-33. 26. Straneo G, Scarpazza G. Efficacy and safety of clarithromycin versus josamycin in the treatment of hospitalized patients with bacterial pneumonia. J Int Med Res 1990; 18: 164-170. 27. Marchi E. Comparative efficacy and tolerability of clarithromycin and amoxicillin in the treatment of outpatients with acute maxillary sinusitis. Curr Med Res Opin 1990; 12: 19-24. 28. Levenstein JH. Clarithromycin versus penicillin in the treatment of streptococcal pharyngitis. J Antimicrob Chemother 1991; 27(Suppl A):67-74. 1025
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29. Poirier R. Comparative study of clarithromycin and roxithromycin in the treatment of community-acquired pneumonia. J Antimicrob Chemother 1991; 27(Suppl A):109-116. 30. Guay DRP, Siepman N, Tanaka SK, et al. Comparative safety and efficacy of clarithromycin and 3 oral cephalosporins in the treatment of outpatients with bacterial bronchitis due to Haemophilus influenzae. Drug Invest 1993; 6:33-41. 31. Department of Health and Human Services. COSTART coding symbols for thesaurus of adverse reaction terms. Rockville, MD: Food and Drug Administration, 1990. 32. Teele DW, Klein JO, Rosner B, and the Greater Boston Otitis Media Study Group. Epidemiology of otitis media during the first seven years of life in children in greater Boston: A prospective, cohort study. J Infect Dis 1989; 160:83-94. 33. Del Beccaro MA, Mendelman PM, Inglis AF, et al. Bacteriology of acute otitis media: A new perspective. J Pediatr 1992; 120:81-84. 34. Mendelman PM, Del Beccaro MA, Mclinn SE, Todd WM. Cefpodoxime proxetil compared with amoxicillin-clavulanate for the treatment of otitis media. J Pediatr 1992; 121:459465. 35. Foshee WS. Loracarbef (LY163892) versus amoxicillin-clavulanate in the treatment of bacterial acute otitis media with effusion. J Pediatr 1992; 120:980-986. 36. Stutman HR, Arguedas AG. Comparison of cefprozil with other antibiotic regimens in the treatment of children with acute otitis media. Clin Infect Dis 1992; 14(Suppl 2):$204$208. 37. Odio CM, Kusmiesz H, Shelton S, Nelson JD. Comparative treatment of augmentin versus cefaclor for acute otitis media with effusion. Pediatrics 1985; 75:819-826. 38. Blumer JL, Bertino JS, Husak MP. Comparison of cefaclor and trimethoprimsulfamethoxazole in the treatment of acute otitis media. Pediatr Infect Dis J 1984; 3:2529. 39. Kenna MA, Bluestone CD, Fall P, et al. Cefixime vs. cefaclor in the treatment of acute otitis media in infants and children. Pediatr Infect Dis J 1987; 6:992-996. 40. Marchant CD, Shurin PA, Johnson CE, et al. A randomized controlled trial of amoxicillin plus clavulanate compared with cefaclor for treatment of acute otitis media. J Pediatr 1986; 109:891-896.
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