clavulanate in children with acute otitis media

CLINICAL THERAPEUTICSVVOL.

23, NO. 2,200l

Cefprozil Versus High-Dose AmoxicillinKlavulanate Children with Acute Otitis Media

in

James A. Hedrick, MD,’ Lawrence D. Sher, MD,2 Richard H. Schwartz, MD,3 and Phillip Pierce, MD4 ‘Kentucky Pediatric/Adult Research, Bardstown, Kentucky, ‘Peninsula Research Associates, Inc, Rolling Hills Estates, California, 31nova Fairfax Hospital for Children, Falls Church, Virginia, and 4Bristol-Myers Squibb Company, Wallingford, Connecticut

ABSTRACT

Background: The recommendation of the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group that high-dose amoxicillin, with or without clavulanate, be used to treat acute otitis media (AOM) addressed concerns about the efftcacy of existing therapies against drug-resistant S pneumoniae. This recommendation relied on pharmacodynamic predictions of concentrations of amoxicillin in middle-ear fluid remaining higher than minimum inhibitory concentrations against intermediately resistant Spneumoniae for ~40% of the dosing interval. Objective: This study compared the tolerability and efficacy of cefprozil and high-dose amoxicillinklavulanate in patients with AOM. Methods: Patients were randomized to receive 10 days of investigator-blinded oral treatment with either cefprozil suspension (30 mg/kg/d in 2 divided doses) or amoxicillin/ clavulanate (4Y6.4 mg/kg/d) plus amoxicillin (45 mg/kg/d) in 2 divided doses. The primary efficacy end point was the clinical cure rate 4 to 7 days after the end of treatment. Clinical response by age (6 months-c2 years vs ~2-7 years), disease severity, and unilateral versus bilateral ear infection was also examined. The primary measures of tolerability were the frequency and severity of adverse events and their relation to study drug. Adverse events were either spontaneously reported or elicited during examination and questioning of the patient. Identified adverse events were coded and recorded using the COSTART (Coding Symbols for Thesaurus of Adverse Reaction Terms) system. Results: Three hundred four children between the ages of 6 months and 7 years with 21 sign or symptom of AOM were enrolled in the study, and 303 (150 cefprozil, 153 amoxicillinklavulanate) were treated. Twenty-three patients in each treatment group were not evaluable; thus, 257 children were included in the analysis of evaluable patients. Clinical cure rates were 87% (110/127) with cefprozil and 89% (116/130) with amoxicillin/ Accepted

for publication

January

72, 2001.

Printed in the USA. Reproduction in whole or part is not permitted.

0149-2918/01/$19.00

193

CLINICAL THERAPEUTICS@

clavulanate (95% CI for the difference in cure rate, -10.7% to 4.1%). No betweengroup differences in efficacy were noted by age, disease severity, or unilateral or bilateral involvement. The overall incidence of drug-related adverse events was significantly lower with cefprozil than with amoxicillinklavulanate (19% vs 32%, respectively; P = 0.008), as was the incidence of diarrhea (9% vs 19%, respectively; P = 0.021). Adverse events prompted discontinuation of therapy in 4 (3%) cefprozil patients and 8 (5%) amoxicillinklavulanate patients. Conclusions: Based on a search of MEDLINE@, this study is the first direct comparison of cefprozil versus high-dose amoxicillinklavulanate. Cefprozil was as effective as high-dose amoxicillinklavulanate, with a lower incidence of adverse events. Key words: acute otitis media, cefprozil, amoxicillinklavulanate. (C&z Thel: 2001;23: 193-204)

INTRODUCTION Between 1990 and 1999, the number of office visits for acute otitis media (AOM) in the United States rose from an estimated 24.5 million to >30 million. 1Based on 1995 estimates, the annual cost of AOM in the United States may be as high as $4 billion.2 Both viral and bacterial pathogens have been isolated from the middle-ear fluid of children with AOM. In a review of 9 studies from 1982 to 1996,3 viruses or viral antigens were isolated in 195 of 1024 children (19%; range, 8%-25%). In the majority of these cases, a virus was found to be associated with bacterial pathogens. A virus alone was identified in 51 of the children (5%; range, 0%-15%).

194

Among causative bacterial pathogens identified in AOM, the 3 most common are Streptococcus pneumoniae, accounting for 20% to 50% of cases; Haemophilus infZuenzae, accounting for 10% to 30%; and Moraxella catarrhalis, accounting for 5% to 20%.4-9 Antibiotic resistance among isolates of S pneumoniae, H injluenzae, and M catarrhaEis has complicated treatment,6,7 but the greatest clinical concern is the emergence of penicillin-resistant strains of S pneumoniae. 16,8*9Two surveillance studies of S pneumoniae isolates from medical centers and outpatients in the United States conducted between January 1997 and April 1998 reported overall penicillin resistance rates of 29.5%i” and 50.4%” (intermediately resistant, 17.4%l” and 17.9%,” respectively;resistant, 12.1%l” and 32.5%,” respectively). In both studies, the highest penicillin resistance rates were found among isolates from middleear specimens and from children aged ~10 years. In response to declining in vitro activity of the antibiotics commonly used against S pneumoniae infection and resulting questions about the effectiveness of amoxicillin 45 mg/kg per day in the treatment of AOM, the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group has articulated guidelines that recommend use of high doses of amoxicillin (80-90 mg/kg/d), with or without clavulanate.9~‘2 Based on pharmacodynamic modeling predicting middleear concentrations of amoxicillin exceeding the minimum inhibitory concentration against intermediately resistant S pneumoniae for >40% of the dosing intervaL9*i3 this treatment is expected to result in improved efficacy rates. However, there are limited data on the efficacy of the

J.A. HEDRICK ET AL.

higher dose of amoxicillin compared with standard doses of other commonly used antibiotics. Compared with the established formulation (45 mg/kg/d), the higher dose of amoxicillin has been linked to relatively high rates of adverse experiences, including vomiting (19.7%), contact dermatitis (diaper rash) (l&l%), and diarrhea ( 10.9%).13 Cefprozil is a semisynthetic, broadspectrum, orally administered cephalosporin indicated for the treatment of AOM.14*15 In vitro, cefprozil is active against the 3 most common pathogens in AOM, including many strains of S pneumoniue with intermediate resistance to penicillin.i6*” In a study of the efficacy of cefprozil in patients with persistent or recurrent otitis media or failure of recent antimicrobial therapy, the pathogens identified by tympanocentesis were similar to those found in patients with recently diagnosed untreated AOM, although the isolated pathogens frequently had reduced susceptibility to penicillin or produced beta-lactamase.‘* Nevertheless, >75% of patients achieved a satisfactory clinical response with cefprozil at the end of therapy. In clinical trials, cefprozil 15 mg/kg twice daily was as effective as standard-dose amoxicillin/clavulanate and was better tolerated,15,19-21 causing significantly less diarrhea (P < 0.001). 19,20Adverse events observed most often with cefprozil in patients with AOM are nausea (3.5%) and diarrhea (2.9%)” The beta-la&&beta-lactamase-inhibitor combination amoxicillin/clavulanate is a recommended alternative for refractory AOM 9,22-24 with activity against penicillin-intermediate and penicillin-resistant strains of S pneumoniae.“~24~25 Pharmacodynamic modeling suggests that highdose amoxicillin/clavulanate may reach

concentrations in middle-ear fluid that could eradicate resistant strains of S pneumoniae, although this hypothesis has not been tested clinically.6***26 Amoxicillin/ clavulanate is also clinically effective in children with AOM.27,28 The most common treatment-related adverse event with amoxicillin/clavulanate is diarrhea (9%22%) 20,21,2’,28 The present trial was designed to compare the tolerability and efficacy of cefprozil and high-dose amoxicillin/clavulanate in patients with AOM.

PATIENTS

AND METHODS

This was a multicenter, randomized, investigator-blinded comparative trial, in which patients were stratified by age (6 months-<2 years and ~2-7 years) at randomization. Parents or guardians provided written informed consent.

Inclusion and Exclusion Criteria Eligible patients were aged 6 months to 7 years at enrollment and had al of the following clinical signs and findings on pneumatic otoscopy: ear pain or earache (including tugging or rubbing the ear), ear fullness, discharge from the external auditory canal, or decreased hearing; bulging of the tympanic membrane (erythema could be present, but redness alone was inadequate), loss of normal light reflex and landmarks, or abnormal mobility due to pus or fluid behind the membrane, and edema of the membrane. The following were reasons for exclusion: >2 episodes of AOM (excluding current episode) in the past 6 months; tympanostomy tube(s) in the affected ear(s); spontaneous perforation of the tympanic membrane of >48 hours’ duration; otitis

CLINICAL

externa in the involved ear(s); isolated nonpurulent middle-ear effusion; any systemic antibiotic use in the 7 days before enrollment or the likelihood of such therapy (including prophylaxis) for another infection in the course of the study; craniofacial abnormalities associated with prolonged middle-ear effusion (Down syndrome or cleft palate); serious underlying disease (mastoiditis or cystic fibrosis); phenylketonuria; concomitant infection that would impair assessment of the response to study medication; significant or suspected hypersensitivity reaction to any cephalosporin, beta-lactam antibiotic, or penicillin; renal insufficiency (creatinine clearance ~30 mL/min); malabsorption syndromes or other gastrointestinal disturbances affecting drug absorption; treatment with any other investigational drug within 1 month before enrollment; and previous enrollment in this study.

Treatment and Assessment Patients were treated for 10 days with either cefprozil oral suspension (30 mg&/d) in 2 divided doses (maximum daily dose, 1000 mg) or oral amoxicillin/clavulanate suspension (45/6.4 mg/kg/d) plus amoxicillin (45 mg/kg/d) in 2 divided doses (maximum daily dose, 3600/256 mg). Parents or guardians were given bottles of the appropriate medication and clear instructions for administration and storage. The first dose was administered in the office. The second dose of both regimens was given r8 hours after the first dose on the first day or on the following morning. If the second dose was deferred to the morning of day 2, the last dose was to be administered on day 11. At the first visit, inclusion and exclusion criteria were assessed, a history was obtained, and a physical examination was

196

THERAPEUTICS”

performed. Signs and symptoms of AOM (irritability, ear tugging, redness, and bulging of the tympanic membrane) were rated on a scale from 0 (absent) to 3 (severe). Patients’ body temperature was taken and scored on the following scale: 1 = 38.O”C to 38.5”C; 2 = 38.6”C to 39.O”C; and 3 = >39.O”C. Baseline symptom severity was determined by total score, as follows: <3 = mild disease; 3 to 7 = moderate disease; 8 to 15 = severe disease.29 Between days 4 and 6 of therapy, patients returned to study sites for repeat physical examination, assessment of clinical signs and symptoms, bilateral pneumatic otoscopy, assessment of adverse events, and evaluation of medication use. Adverse events were either spontaneously reported or elicited during questioning and examination of the patient. All identified adverse events were recorded and described using the primary COSTART (Coding Symbols for Thesaurus of Adverse Reaction Terms) classification system for adverse clinical events.‘O Patients were also seen 4 to 7 days after the end of treatment (test-of-cure visit), at which time on-therapy evaluations were repeated. Investigator assessment of clinical response was also conducted at this visit. The primary efficacy end point was the clinical cure rate 4 to 7 days after the end of treatment. Clinical response by age (6 months-<2 years vs ~2-7 years), disease severity, and unilateral versus bilateral infection was also examined. The following categories of clinical response were used: cured-resolution or improvement in primary signs/symptoms (ear pain, earache, bulging of tympanic membrane) in both ears without the need for additional systemic antibiotics; failure-either the primary signs/symptoms were unchanged or worse, the symptoms

J.A. HEDRICK ET AL.

had resolved but another systemic antibiotic was added, or new primary signs/ symptoms had developed in a previously uninvolved ear; and unable to determineno follow-up visit. The primary tolerability end points were the frequency and severity of adverse events and their relationship to study medications, as determined by the investigator. Statistical Analysis Assuming an 85% clinical cure rate for evaluable patients in each treatment group, 120 patients per arm were required to give 290% power to claim noninferiority of cefprozil to high-dose amoxicillinklavulanate (ie, the lower bound of the 95% CI for the difference in cure rates [cefprozil - highdose amoxicillinklavulanate] is r-15). Assuming an 80% evaluability rate, - 150 patients were required to be randomized per treatment arm (300 patients total). Eligible patients had signs and symptoms consistent with otitis media, appropriate pneumatic otoscopic findings, and s2 episodes of otitis media in the previous 6 months, excluding the current episode. For inclusion in the clinically evaluable population, patients had to meet the definition of eligibility; receive study drug for ~3 days; undergo posttreatment assessment of clinical response (4-7 days after the end of treatment); and receive no systemic antibacterial agent active against common respiratory pathogens for an infection other than AOM from enrollment to the posttreatment visit. Demographic and baseline clinical data were summarized by treatment group. Categoric variables were summarized by numbers and percentages of patients in each category.

The primary efficacy analysis compared the posttreatment clinical responses to cefprozil and amoxicillinklavulanate in clinically evaluable patients. A 95% CI adjusted for age (6 months-c2 years vs ~2-7 years) was calculated around the difference in cure rates. Cefprozil was considered effective relative to high-dose amoxicillinklavulanate if the lower boundary of the CI for the difference in rates (cefprozil - high-dose amoxicillinklavulanate) was r-15. Secondary analyses involved clinical response by age, disease severity, and unilateral versus bilateral infection. All results were analyzed for eligible (modified intent-to-treat) as well as evaluable patients. All patients who received rl dose of study drug were included in the analysis of tolerability. Selected drug-related adverseevent rates in the 2 groups were compared using the Fisher exact test, with statistical significance set at P < 0.05.

RESULTS Three hundred four patients were enrolled in the study, 303 of whom were treated (150 cefprozil, 153 amoxicillinklavulanate). The percentages of males and females were 45% and 55%, respectively, in the cefprozil group and 60% and 40%, respectively, in the amoxicillinklavulanate group. The median age of patients in both groups was 2.0 years. The mean age of the patients in each treatment group and the severity of each symptom and overall disease were generally comparable between groups (Table I). In each group, 23 patients were not evaluable. Reasons for exclusion from evaluation included treatment with <6 or ~24 doses (10 in each treatment group), assessment of the clinical response outside the test-of-cure window or no test-of-cure

197

CLINICAL THERAPEUTICS”

assessment (8 cefprozil, 6 amoxicillin/ clavulanate), ineligibility of patient (4 and 7, respectively), and presence of tympanostomy tubes (1 cefprozil). Nine patients (6%) in the cefprozil group and 11 patients (7%) in the amoxicillinklavulanate group discontinued treatment prematurely (Table II).

Table I. Characteristics

A mean of 19.5 doses of cefprozil and 19.1 doses of amoxicillinklavulanate were administered for a mean of 10.3 and 10.2 days, respectively. Fourteen patients (9%) in the cefprozil group and 15 patients (10%) in the amoxicillinklavulanate group received additional concomitant nonsystemic antimicrobial agents.

of patients treated with study drug. Cefprozil (n = 150)

Sex,

no. (%)

Male Female Mean age, y (SD) Age group, no. (%) <2 Y 22 Y Mean body weight, kg (SD) Overall disease severity, no. (%) Mild Moderate Severe Infection site, no. (%) Unilateral Bilateral Acute otitis media within 6 months, no. (%) No Yes Symptom, no. (%) Ear pain Irritability Ear fullness Decreased hearing Fever Otoscopic findings, no. (%) Redness Bulging Immobility Loss of light reflex/landmarks Opacity Retraction

198

AmoxicillinKlavulanate (n = 153)

68 (45) 82 (55) 2.5 (2.0)

92 (60) 61 (40) 2.4 (1.9)

70 (47) 80 (53) 14.5 (6.2)

76 (50) 77 (50) 14.4 (6.0)

1 (
2 (1)

87 (58) 62 (41)

104 (68) 47 (31)

98 (65) 52 (35)

80 (52) 73 (48)

67 (45) 83 (55)

67 (44) 86 (56)

135 129 94 36 22

(90) (86) (63) (24) (15)

141 119 95 30 33

(92) (78) (62) (20) (22)

144 135 134 136 100

(96) (90) (89) (91) (67)

147 133 142 136 112

(96) (87) (93) (89) (73)

10 (7)

13 (8)

J.A. HEDRICK ET AL.

Table II. Reasons for discontinuation. No. (%) of Patients Amoxicillin/Clavulanate (n = 153)

Cefprozil (n = 150) Adverse event Therapy ineffective Patient request Protocol violation

8 (5) 3 (2) -

4 (3) 3 (2) 1 (cl) 1 (cl)

m Cefprozil 0 AmoxicilWdavulanate

r 93%

80.

80% I

20, 0

64) 6 months to ~2 years (n = 59) (n =

92%

-

(n = 68) (n = 66) 22 to 7 years

Age

Figure 1. Clinical

cure rates in evaluable

Clinical Response At the test-of-cure visit, 87% (110/127) of evaluable cefprozil patients and 89% ( 116/ 130) of evaluable amoxicillinklavulanate patients were cured (95% CI for the difference in cure rate, -10.7% to 4.1%). Among all eligible patients (modified intent-to-treat), respective cure rates were 86% (125/146) and 88% (128/146) (95% CI for the difference in cure rate, -10.6 to 4.6).

patients, stratified by age. Cefprozil and amoxicillinklavulanate demonstrated comparable efficacy in evaluable patients when analyzed by age (Figure 1). No notable significant between-treatment differences in cure rates were evident when evaluable patients were analyzed by baseline severity of disease (Figure 2) or unilateral or bilateral involvement (Figure 3). Comparably high cure rates were noted in the 115 patients who had experienced no episodes of AOM in the 6 months before enrollment: 90% (52/58) with cefprozil and

199

CLINICAL THERAPEUTICS”

WCefprozil 0 Amoxicillinklavulanate

(n = 75) (n = 90)

(n = 51) (n = 39)

Moderate

Severe

Figure 2. Clinical cure rates in evaluable patients with moderate or severe acute otitis media. (One patient in each group had mild disease; both were cured.) n

Cefmozil 0 Am~xicillinfclavulanate 82%

(n=82)(n=71) Unilateral

Figure 3. Clinical media.

cure rates in evaluable

96% (S/57) with amoxicillinklavulanate. Among the 142 patients (69 cefprozil, 73 amoxicillinklavulanate) who had experienced 1 to 3 episodes of AOM over that period, 84% of each group (58 and 61, respectively) were clinically cured. Tolerability The overall incidence of drug-related adverse events was significantly lower in chil-

200

85%

(n = 45) (n = 59) Bilateral

patients with unilateral

or bilateral

acute otitis

dren treated with cefprozil (19%) than in those treated with amoxicillinklavulanate (32%) (P = 0.008). Adverse events led to study discontinuation in 4 patients (3%) treated with cefprozil and 8 patients (5%) treated with amoxicillin/clavulanate. Diarrhea, vomiting, and rash were the most frequently reported adverse events with both drugs, although the incidence of each was higher with amoxicillin/

J.A. HEDRICK ET AL.

Table III. Drug-related

adverse events occurring

in ~2% of patients. No. (%) of Patients

Cefprozil (n = 150)

Amoxicillinklavulanate (n = 153)

All events Diarrhea

28 (19) 14 (9)

49 (32)* 29 (19)+

Vomiting Rash

3 (2) 9 (6)

9 (6) 16 (10)

"P = 0.008versus cefprozil. +P = 0.021 versus cefprozil.

clavulanate (Table III). Patients treated with cefprozil had a significantly lower incidence of diarrhea than patients treated with amoxicillinklavulanate (9% vs 19%, respectively; P = 0.021).

DISCUSSION Based on the results of a MEDLINE@ search, the present study is the first direct comparison of cefprozil and high-dose amoxicillinklavulanate in children with AOM. This controlled trial demonstrated comparability in the efficacy of cefprozil and high-dose amoxicillinklavulanate for the treatment of AOM in patients ranging in age from 6 months to 7 years. Overall clinical cure rates approached 90% in both groups. Efficacy was comparable when the results were analyzed by age, severity of disease, and involvement of 1 or both ears. Cefprozil was better tolerated than high-dose amoxicillinklavulanate, which produced significantly higher incidences of overall drug-related adverse events (P = 0.008) and diarrhea (P = 0.021). The diagnosis of AOM in clinical practice is typically based on pneumatic otostympanocentesis is copy. 1,3’ Although definitive and is encouraged, especially

when treatment fails,32 the procedure is not often used in patients who do not have recurrent disease. The design of this study accords with clinical practice in basing diagnosis on the results of otoscopy and the presence of signs and symptoms of AOM, and basing the findings strictly on clinical outcomes. Given the increasing prevalence of resistant S pneumoniae, recent guidelines recommend high-dose amoxicillin (80-90 mg/kg/d) for the initial empiric treatment of AOM.9,22,23 This recommendation is based largely on microbiologic data and the results of pharmacokinetic/pharmacodynamic modeling. 9,23 High doses of amoxicillin are effective in AOM,13 although there is no clinical evidence to support superior clinical efficacy compared with standard doses.*3,23 Despite potentially limited tolerability, there is consensus on the use of amoxicillin as first-line therapy for pediatric AOM.23,33,34The choice of drug when initial therapy has failed is less certain.34 Recommended alternatives include amoxicillin/ clavulanate, cefuroxime axetil, and intramuscular ceftriaxone.9 Other authors have suggested antibiotics such as cefprozil and cefpodoxime proxetil,23 as well as third-

201

CLINICAL THERAPEUTICS@

generation cephalosporins and newer macrolides.25 When using amoxicillin/ clavulanate, a higher dose of the amoxicillin component is suggested.9 The clinical efficacy of cefprozil in pediatric AOM demonstrated in this trial is consistent with other clinical results. In 4 trials involving more than 1400 children with AOM,i9-*’ cefprozil20 to 30 mg/kg per day was compared with amoxicillin/clavulanate 40 mg/kg per day,19-*l cefixime 8 mg/kg per day,20 and cefaclor 40 mg/kg per day,*O and achieved clinical response rates comparable to those with the other agents. In one of the clinical trials comparing cefprozil with amoxicillin/clavulanate,19 treatment failures attributable to persistent symptoms, posttreatment isolation of the original pathogen, or superinfection occurred significantly more often with amoxicillin/ clavulanate than with cefprozil (P = 0.05). Although the ability to eradicate pathogens, including penicillin-resistant strains of S pneumoniae, is an important criterion in antibiotic selection, clinical cure and tolerability are the primary considerations.23,24 This study was not designed to compare the microbiologic eradication of pathogens by cefprozil and high-dose amoxicillin/clavulanate in patients with AOM. Some differences in activity may exist between these agents; however, no such differences were reflected by differences in efficacy between treatment groups. Gastrointestinal symptoms are the most troublesome side effects in children treated with amoxicillin or cephalosporins,24 and constituted the most common drug-related adverse events in both groups in the present study. Cefprozil, however, produced a significantly lower incidence of drug-related diarrhea than did amoxicillin/clavulanate (P = 0.021). This finding confirms previous reports of fewer episodes of diarrhea with

202

cefprozil than with amoxicillin/clavulanate (8% vs 35%, respectively,t9 and 7% vs 22%, respectively20; both, P s 0.001).

CONCLUSIONS Cefprozil is an effective alternative to high-dose amoxicillin/clavulanate for the empiric treatment of AOM in pediatric patients. In the patients studied in this trial, cefprozil 30 mg/kg per day given in 2 divided doses exhibited similar efficacy to and significantly better tolerability than that of amoxicillin/clavulanate 4516.4 mg/kg per day plus amoxicillin 45 mg/kg per day given in 2 divided doses.

ACKNOWLEDGMENTS Funding was provided by Bristol-Myers Squibb Company, Princeton, New Jersey. The following individuals participated in and/or contributed to the development and completion of this study: Jeffrey Adelglass, MD; Vincent L. Annino, BS; Gerson H. Aronovitz, MD; Mark M. Blatter, MD; Juan A. Bonilla, MD; Willis Manford Gooch III, MD; Samuel E. McLinn, MD; Janak Patel, MD; Michael E. Pichichero, MD; Seth Reiner, MD; Gary Ruoff, MD; Rene Russo, PharmD; and Karen Skuba, MS.

REFERENCES Klein JO. Clinical implications of antibiotic resistance for management of acute otitis media. J Lab Clin Med. 2000;135: 220-224. Berman S. Otitis media in children. N Engl JMed. 1995;332:1560-1565. Chonmaitree T, Heikkinen T. Role of viruses in middle-ear disease. Ann New York Acad Sci. 1997;830:143-157.

J.A. HEDRICK ET AL.

4. Klein JO. Otitis media. Clin Infect Dis. 1994;19:823-833. 5. Ruuskanen 0, Heikkinen T. Otitis media: Etiology and diagnosis. Pediatr Infect Dis J. 1994; 13(Suppl l):S23-S26. 6. Block SL. Causative pathogens, antibiotic resistance and therapeutic considerations in acute otitis media. Pediatr Infect Dis .I. 1997; 16449456. 7. Klein JO. Management of acute otitis media in an era of increasing antibiotic resistance. Int J Pediatr Otorhinolaryngol. 1999;49(Suppl l):S15-s17. 8. Infectious Diseases and Immunization Committee. High dose amoxicillin: Rationale for use in otitis media treatment failures. Paediatr Child Health. 1999;4:321323. 9. Dowel1 SF, Butler JC, Giebink GS, et al. Acute otitis media: Management and surveillance in an era of pneumococcal resistance-a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J. 1999;18:1-9. 10. Doem GV, Brueggemann AB, Huynh H, et al. Antimicrobial resistance with Streptococcuspneumoniae in the United States, 1997-98. Emerg Infect Dis. 1999;5:757765. 11. Jacobs MR, Bajaksouzian S, Zilles A, et al. Susceptibilities of Streptococcus pneumoniae and Haemophilus influenzae to 10 oral antimicrobial agents based on pharmacodynamic parameters: 1997 U.S. surveillance study. Antimicrob Agents Chemother: 1999;43:1901-1908. 12. McConaghy JR, Smith SR. Controversy in otitis media management: Should we follow the CDC recommendations? Am Pam Phys. 2000;61:317-3 18.

13. Bottenfield GW, Burch DJ, Hedrick JA, et al. Safety and tolerability of a new formulation (90 mg/kg/day divided every 12 h) of amoxicillin/clavulanate (Augmentin@) in the empiric treatment of pediatric acute otitis media caused by drug-resistant Streptococcus pneumoniae. Pediatr Infect Dis J. 1998;17:963-968. 14. Physicians’ Desk Reference@. 54th ed. Montvale, NJ: Medical Economics Company, Inc; 2000:822-825. 15. Wiseman LR, Benfield P. Cefprozil. A review of its antibacterial activity, pharmacokinetic properties, and therapeutic potential. Drugs. 1993;45:295-317. 16. Barriere SL. Review of in vitro activity, pharmacokinetic characteristics, safety, and clinical efficacy of cefprozil, a new oral cephalosporin. Ann Pharmacother. 1993;27:1082-1089. 17. Nelson CT, Mason EO Jr, Kaplan SL. Activity of oral antibiotics in middle ear and sinus infections caused by penicillinresistant Streptococcus pneumoniae: Implications for treatment. Pediatr Infect Dis J. 1994;13:585-589. 18 Pichichero ME, McLinn S, Aronovitz G, et al. Cefprozil treatment of persistent and recurrent acute otitis media. Pediatr Infect Dis J. 1997;16:471-475. 19. Arguedas AG, Zaleska M, Stutman HR, et al. Comparative trial of cefprozil vs. amoxicillin clavulanate potassium in the treatment of children with acute otitis media with effusion. Pediatr Infect Dis J. 1991;10:375-380. 20. 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):S204-S208.

203

CLINICAL THERAPEUTICS”

21 Gehanno P, Berche P, Boucot I, et al. Comparative efficacy and safety of cefprozil and amoxycillin/clavulanate in the treatment of acute otifis media in children. JAntimicrob Chemothel:

28.

Efficacy of amoxicillin/clavulanate for acute otitis media: Relation to Streptococcus pneumoniae

29.

23. Aronovitz GH. Antimicrobial therapy of acute otitis media: Review of treatment recommendations. Clin The,: 2000;22:29-39. 24. Hoppe HL, Johnson CE. Otitis media: Focus on antimicrobial resistance and new treatment options. Am J Health-Syst Pharm.

Arch Fam Med.

30.

Dagan R, Leibovitz E, Greenberg D, et al. Early eradication of pathogens from middle ear fluid during antibiotic treatment of acute otitis media is associated with improved clinical outcome. Pediatr Infect

COSTART-Coding

Symbols

saurus of Adverse Reaction

31.

Steele RW. Management Infect Med.

The-

of otitis media.

1998;15:174-178,203.

1999;8:68-78. 32. Pichichero

15:255-259.

27. Hoberman A, Paradise JL, Burch DJ, et al. Equivalent efficacy and reduced occurrence of diarrhea from a new formulation of amoxicillin/clavulanate potassium (Augmentin@) for treatment of acute otitis media in children. Pediatr Infect Dis J.

Improving

ME. Acute otitis media: Part I. diagnostic accuracy. Am Fam

Phys. 2000;61:205

I-2056.

33.

Pichichero ME. Acute otitis media: Part II. Treatment in an era of increasing antibiotic resistance. Am Fam Phys. 2000; 61:2410-2416.

34.

Klein JO. Review of consensus reports on management of acute otitis media. Pediatr Infect Dis J. 1999;18:1152-1155.

Address correspondence to: James A. Hedrick, MD, Kentucky Pediatric/Adult 201 S. Fifth Street, Bardstown, KY 40004. E-mail: [email protected]

204

for

Terms. 5th ed.

Rockville, Md: US Food and Drug Administration; 1995.

26. Craig WA, Andes D. Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. Pediatr Infect Dis J. 1996;

1997;16:463-470.

Pediatr In-

Dis J. 1998; 17:776-782.

1998;55:1881-1897.

25. Block SL. Strategies for dealing with amoxicillin failure in acute otitis media.

susceptibility.

fect Dis J. 1996;15:955-962.

1994;33:1209-1218.

22. Holten KB, Onusko EM. Appropriate prescribing of oral beta-lactam antibiotics. Am Fam Phys. 2000;62:61 l-620.

Hoberman A, Paradise JL, Block S, et al.

Research,