Question

• A 15 month old male presents after completing 7 of 10 days of Amoxicillin for acute otitis media (AOM).  He remains irritable and persistently febrile.  Clinical exam is consistent with worsening otitis, but he is otherwise non-toxic appearing.  Parents are leery of initiating a second course of oral antibiotics.  Is single dose Ceftriaxone more effective than other second-line therapies in terms of resolution of otitis media?  Is there a higher incidence of resistance following therapy?

Clinical Bottom Lines

1. In populations of known/suspected pneumococcal resistance, a single dose of intramuscular Ceftriaxone (50mg/kg) appears to be as effective as a 10 day course of Augmentin in clinical resolution of AOM.¹
2. The chance of a child carrying Penicillin-resistant Streptococcus pneumoniae (PRSp) did not increase after treatment with Ceftriaxone.
3. There is no evidence that a single dose of Ceftriaxone contributed more to emergence of resistance than 10 days of oral Augmentin.

Summary of Key Evidence

1. Prospective, comparative, open randomized multicenter trial taking place in France over 15 month period.  Study population included children ages 4-30 months, residing in known area with high rate of PRSp, with new diagnosis of AOM.
2. Diagnostic criteria for AOM: presence of effusion with marked redness/bulging of tympanic membrane OR moderate redness/bulging associated with fever/otalgia/irritability.  Exclusion criteria: receipt of antibiotic treatment within 7 days before study enrollment, history of beta lactam sensitivity, severe otic disease, presence of complications of otitis.
3. Treatment (Ceftriaxone 50mg/kg IM x 1 vs. Augmentin 80mg/kg/d divided TID x 10 days) assigned via telephonic computer-generated code.  Return visits scheduled on days 12-14 (main endpoint) and 28-42 after beginning treatment for AOM.  Nasopharyngeal swab for bacterial culture obtained before treat and days 12-14 to evaluate carriage of Streptococcus pneumoniae (S. pneumo), Hemophilus influenzae (H. flu), and Moraxella catarrhalis (M. Catarrhalis).
4. Outcome measures included evaluation of clinical response on days 12-14--success vs. failure of the individual treatment, equivalence of clinical response with respect to two treatments (difference in success rates between two groups not to exceed 10%), rates of continued success, change in nasopharyngeal flora, adverse events.  (Success= clinical cure + improvement; failure= continued fever, persistent or worsening otoscopic signs, development of complications, requirement of antibiotic other than study drug.)
5. 513 patients were randomized to receive Ceftriaxone (n=255) or Augmentin (n=258).  463 patients Ceftriaxone= 235, Augmentin= 228) were successful in being evaluated n the "per protocol" efficacy analysis at the first f/u visit.  There were no significant differences in clinical characteristics in the two groups.
6. At the main end point (days 12-14), in the per protocol population, 79.2% patients in Augmentin group maintained clinical success.  For normalization of tympanogram curves at days 28-42, in per protocol group, Ceftriaxone= 49.3% vs. Augmentin 45.2%.  Using their definition of equivalence (difference in success rates between the two treatment groups not to exceed 10%), the data suggests treatment equivalence.
7. Before treatment, no significant differences were found between the two treatment groups with respect to carriage rates of S. pneumo, H. flu, M. catarrhalis.  Percentages of beta lactamase producing strains of H. flu and M. catarrhalis after treatment were not significantly different.  Post-treatment, carriage of PRSp for Ceftriaxone and Augmentin was 63% and 83% respectively.  This difference appears to be reflection of dramatic decrease in penicillin susceptible strains in Augmentin group.  Looking at raw data, the actual chance for a child to carry intermediate or highly resistant strains did not increase.
8. Adverse events for Ceftriaxone= 14.1% vs. Augmentin 30.6%.  Main events recorded:  gastrointestinal complaint, rash.

Additional Comments

• Acute otitis media is difficult to investigate because of wide variations in diagnostic criteria and measurements of outcome.  However, the authors chose to simulate an outpatient practice with clinical criteria of fever, otalgia, and irritability combined w/ otoscopic findings--discoloration, bulging.
• Several studies have documented the effectiveness of one IM dose of Ceftriaxone (50mg/kg) for the initial treatment of AOM.
• Middle ear fluid penetrance characteristics and its long half-life are favorable for time-dependent killing by Ceftriaxone.
• Although the most common causative bacteria in AOM are also isolated in nasopharyngeal culture, the positive predictive value is poor for bacteriologic diagnosis of AOM.  However, use of nasopharyngeal culture has been demonstrated as useful in monitoring changes in resistance of "potential" otic pathogens.
• Although Ceftriaxone is not "first line" therapy for AOM, consideration for its usefulness in geographic areas of high penicillin resistance/individual w/ persistent infection presumed to be secondary to resistant organisms, can be given.
• Adverse events include rash and less often GI complaints.

Citation

1. Cohen R, Navel M, Grunberg J, et al.  One dose ceftriaxone vs. ten days of amoxicillin/clavulanate therapy for acute otitis media: clinical efficacy and change in nasopharyngeal flora.  Pediatric Infectious Disease Journal 1999; 18: 403-9.
2. Carlin S, Marchant C, Shurin P, et al.  Host factors and early therapeutic response in acute otitis media.  Journal of Pediatrics 1991; 118: 178-83.
3. Dagan R, Abramson O, Leibovitz E, et al.  Impaired bacteriologic response to oral cephalosporins in acute otitis media caused by pneumococci with intermediate resistance to penicillin.  Pediatric Infectious Disease Journal 1996; 15: 80-85.
4. Gehanno P, Lenoir G, Barry B, et al.  Evaluation of nasopharyngeal cultures for bacteriologic assessment of acute otitis media in children. Pediatric Infectious Disease Journal 1996; 15: 329-332.
5. Gehanno P, Nguyen L, Barry B, et al.  Eradication by ceftriaxone of streptococcus pneumoniae isolates with increased resistance to penicillin in cases of acute otitis media.  Antimicrobial Agents and Chemotherapy 1999; 43: 16-20.
6. Green S, Rothrock S.  Single-dose intramuscular ceftriaxone for acute otitis media in children.  Pediatrics 1993; 91: 23-30.
7. Gudnason T, Gudbrandsson F, Barsanti F, et al.  Penetration of ceftriaxone into the middle ear fluid of children.  Pediatric Infectious Disease Journal 1998; 17: 258-260.
8. Reichler M, Allphin A, Breiman R, et al.  The spread of multiply resistant streptococcus pneumoniae at a day care center in Ohio.  Journal of Infectious Diseases 1992; 166: 1346-53.
9. Rosenfeld R, Vertrees J, Carr J, et al.  Clinical efficacy of antimicrobial drugs for acute otitis media: Meta-analysis of 5400 children from thirty-three randomized trials.  Journal of Pediatrics 1994; 124:  355-67.
10. Teele D, Klein J, Rosner B, et al.  Epidemiology of otitis media during the first seven years of life in children in greater Boston:  A prospective, cohort study.  Journal of Infectious Diseases 1989; 160: 83-94.

CAT Author: Naomi Duke, MD

CAT Appraisers: John G. Frohna, MD, MPH

Date appraised: September 1999