PEDIATRIC PHARMACOLOGY AND THERAPEUTICS

Cefpodoxime proxetil compared with amoxicillin-clavulanate for the treatment of otitis media Paul M. M e n d e l m a n , MD,* Mark A. Del B e c c a r o , MD, Samuel E. McLinn, MD, a n d Wesley Mark Todd, MD From the Children's Hospital and Medical Center and the Department of Pediatrics, University of Washington, Seattle, a private pediatric practice, Scottsdale, Arizona, and Upjohn Company, Kalamazoo, Michigan In a multicenter, randomized, investigator-blinded trial, patients were r a n d o m l y selected to receive either c e f p o d o x i m e proxetil or a m o x i c i l l i n - c l a v u l a n a t e potassium orally for the treatment of a c u t e suppurative otitis media. Patients were seen before, during, and at the end of therapy, and 2 to 3 weeks after c o m p l e t i o n of therapy. A total of 229 patients, 153 receiving c e f p o d o x i m e and 76 receiving amoxicillin-clavulanate were entered into the study; all patients were e x a m i n e d to determine drug safety. A total of 146 patients, 98 in the cefp o d o x i m e group and 48 in the amoxicillin-clavulanate group, c o m p l e t e d the study and were e x a m i n e d to d e t e r m i n e drug efficacy. End-of-therapy microbio l o g i c eradication rates in assessable patients were 92% for c e f p o d o x i m e and 86% for amoxicillin-clavulanate ( p = 0.14; 95% c o n f i d e n c e interval [Cl] on difference: -4.4%, 19.2%). End-of-therapy clinical response rates for assessable patients were as follows: cured, 68% for c e f p o d o x i m e and 65% for amoxicillinclavulanate; improved, 24% for c e f p o d o x i m e and 23% for amoxicillin-clavulanate; and failed, 8% for c e f p o d o x i m e and 13% for a m o x i c i l l i n - c l a v u l a n a t e (p = 0.57; 95% Ch -8.4%, 16.5%). Recurrence rates at long-term follow-up were 24% for c e f p o d o x i m e - t r e a t e d patients and 25% for those given amoxicillin-clavulanate. Both drugs were well tolerated; 20.9% of those given c e f p o d o x i m e and 31.6% of a m o x i c i l l i n - c l a v u l a n a t e - t r e a t e d patients had drug-related adverse m e d i c a l events ( p = 0.102; 95% CI: -23,9%, 2.6%). Gastrointestinal complaints were the most frequently reported drug-related side effect in both groups: 11.8% of c e f p o d o x i m e - t r e a t e d patients and 21.1% of those given amoxicillin-clavulanate ( p = 0.076; 95% CI: -20.8%, 2.2%). Drug-related d e r m a t o l o g i c side effects (e.g., d i a p e r rash, pruritus, urticaria) were reported in 7.8% of c e f p o d o x i m e treated patients and 14.5% of those who received a m o x i c i l l i n - c l a v u l a n a t e ( p = 0.160; 95% CI: -16.6%, 3.3%). Our findings suggest that clinical e f f i c a c y for c e f p o d o x i m e administered twice daily is equivalent to that of amoxicillin-clavulanate administered three times a day. (J PEDIATR1992;121:459-65)

Supported in part by Upjohn Company, Kalamazoo, Mich. Submitted for publication Jan. 2, 1992; accepted April 30, 1992. Reprint requests: Mark A. Del Beccaro, MD, Children's Hospital and Medical Center, PO Box C5371, Seattle, WA 98105. *Now at Merck Sharp & Dohme Research Laboratories, West Point, Pa. 9/25/38974

Amoxicillin has been the preferred drug for the treatment of otitis media; however, it is not effective against/3-1actamase-positive pathogens. 1 The increasing prevalence of otitis media caused by t3-1actamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis makes it necessary to consider other drugs for the first-line treatment of otitis media in children in areas in which/3-1acta-

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CI MIC

Confidence interval Minimal inhibitory concentration

The Journal of Pediatrics September 1992

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mase-positive pathogens are prevalent, and for second-line treatment in patients in whom penicillin agents fail. Cefpodoxime proxetil is a new third-generation cephalosporin with a broad spectrum of activity against a wide range of pathogens, including those which cause otitis media. 27 After oral administration the proxetil portion is hydrolyzed from the molecule, leaving the active cefpodoxime moiety. 8 Time to peak plasma concentration and area under the plasma concentration-time curve are equivalent for tablets and suspension. Higher plasma levels are produced when cefpodoxime proxetil is taken with food. 9 The mean serum half-life of cefpodoxime is 2.1 to 2.8 hours, permitting maintenance of therapeutic levels with twice-daily administration.4, 7, 10Cefpodoxime shows excellent tissue penetrationl0, ll and is resistant to most ~-lactamases. 5 The pharmacokinetics and microbiologic characteristics of cefpodoxime make it potentially useful in the treatment of otitis media: its dosing characteristics could offer significant convenience and compliance benefits. Clinical studies in Japan on the use of cefpodoxime in more than 700 children with otitis media have indicated efficacy for this condition. 12 We undertook our study to compare the safety and efficacy of cefpodoxime proxetil versus amoxicillin-clavulanate in the treatment of otitis media in infants and children. METHODS Study design. The study was designed as a multicenter. investigator-blinded, randomized comparison of cefpodoxime and amoxicillin-clavulanate in the treatment of acute suppurative otitis media. Thirteen centers enrolled patients into the study (see the acknowledgments at the end of the text). The study was approved by the institutional review board of each participating institution. Patient selection. Patients aged 2 months to 18 years with signs and symptoms of acute suppurative otitis media were identified as potential study participants. Acute otitis media was defined by compatible tympanic membrane signs of acute suppurative otitis media (either hyperemia, opacity, bulging, or perforation), associated with any one symptom of fever, irritability, or ear pain with a duration of 7 days or less. Girls of child-bearing potential not practicing an acceptable contraceptive method! were excluded from the study. Other exclusion criteria were as follows: (1) hypersensitivity to cephalosporins, cephamycins, ampicillin, amoxicillin, or clavulanic acid; (2) type 1 hypersensitivity to penicillin; (3) antimicrobial therapy within 5 days of study entry (including topical solutions for therapy of otitis

externa), except for antituberculosis therapy; (4) neutropenia (leukocyte count 130 /~mol/L [1.5 mg/dl); (6) hepatic dysfunction (serum alanine aminotransferase level > 110 U / L in infants and >60 U / L in children); (7) history of or present immunologic or neoplastic disease; (8) tympanotomy tubes, cholesteatoma, retraction pockets, and known preexisting sensorineural hearing loss; (9) spontaneous perforation of tympanic membrane >24 hours before study entry; (10) inability to permit tympanocentesis and pneumatic otoscopy and/or tympanometry unless there was a perforation of the tympamc membrane within 24 hours of study entry; and (11) current enrollment in any other investigational protocol or previous enrollment in any cefpodoxime study. Signed informed consent was obtained from the parent or guardian (unless the child was an emancipated minor) and also from the patient if the patient was 12 to l8 years of age. Patient examination. An initial history and physical examination of each patient were obtained before entry into the study. A second physical examination was conducted at the end-of-therapy visit (study day l0 to 14) or at study withdrawal. A standardized otoscopic examination was performed at all centers at all visits (admission, study day 3 to 7. study day 10 to 14, study day 24 to 35) to detect possible hyperemia, opacity, bulging, and light reflex or perforation. Pneumatic otoscopy, tympanometry, or both were also performed at these visits to confirm the presence of effusion; when a perforated tympanic membrane was present at the time of the pretreatment visit, this portion of the examination was not done at this visit. At the pretreatment visit, tympanocentesls was performed to obtain middle ear fluid for microbiologic culture; culture specimens were processed by a certified microbiology laboratory. In cases of bilateral otitis media, if the parents consent er tympanocentesis was performed on each tympanic membrane. Each culture specimen of middle ear fluid was considered separately in subsequent efficacy evaluations. Tympanocentesls was repeated at a subsequent visit only if effusion and clinical signs of infection (i.e.. unchanged or worsening tympanic membrane appearance compared with the previous examination) were present. Tympanocentesis was performed as follows: The external auditory canal was cleansed of cerumen, and a culture specimen from the external ear canal, near the tympanic membrane, was obtained. Some centers also sterilized the ear canal. After~ the culture sample was obtained from the external auditory canal, tympanocentesis was performed with an 18-gauge needle through the anteroinferior quadrant of the tympanic membrane. If tympanic perforation (--~21 mm, resistant ~ 1 7 ram; for amoxicillinclavulanate, susceptible ~ 18 ram, resistant ~< 13 mm (except for Haemophilus and Staphylococcus, for which amoxicillin-clavulanate susceptibility was defined as susceptible ~ 2 0 mm and resistant ~ 19 mm). Pathogens were also sent to a central laboratory at Thomas Jefferson University for cefpodoxime minimal inhibitory concentration testing and confirmation of amoxicillin-clavulanatedisk test results after subculture on chocolate agar slants. The following MIC break points were used for cefpodoxime: susceptible ~8 t~g/ml. The MIC test results were used to determine susceptibility; however, if the test was not performed on an isolate, disk zone data were used. Assessability. To be considered in the efficacy evaluation, patients were required to have no significant deviations from the inclusion and exclusion criteria, to have a pathogenic organism isolated from the admission middle ear effusion culture specimen, to have been infected with a pathogen susceptible to both cefpodoxime proxetil and amoxicillinclavulanate, to have been in compliance with the therapeu-

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T a b l e I. Patient population in the two treatment groups

Age (yr)* Gender (% male) Race (%) White Black Hispanic Asian/other No. (%) of patients with bilateral otitis Pretreatment temperature (~ Previous acute suppurative otitis media (%)

Cefpodoxime (n = 153)

Amoxicillinclavulanate (n = 76)

3.4 • 2.9 54

3.4 + 3.0 53

71 16 9 4 79 (52)

75 13 9 2 44 (58)

99.9 _+ 2.1

99.7 + 2.1

81

83

T a b l e II. Microbiologic results in all patients Pathogens isolated Pathogen

No.

%

(%)

Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Streptococcus pyogenes Staphylococcus aureus Staphylococcus hominis Escherichia hermanii Acinetobacter anitratus

84 47t 36t

45 25 19

100 100 94

13

7

1O0

2 2

1 1

100 100

1 1

Cefpodoxime proxetil compared with amoxicillin-clavulanate for the treatment of otitis media.

In a multicenter, randomized, investigator-blinded trial, patients were randomly selected to receive either cefpodoxime proxetil or amoxicillin-clavul...
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