Candice E. Johnson

Measuring the comparative efficacy of antibacterial agents for acute otitis media: The “Pollyanna phenomenon”

In randomized, double-blind trials of antibiotic therapy for acute otitis media that determined both clinical and bacteriologic outcomes, clinical success rates were (93%) 236 of 253 for patients with bacteriologic success, (62%) 25 of 40 for those with bacteriologic failure, and (80%) 124 of 155 for those with nonbacterial acute otitis media. These rates were used to calculate the effectiveness of three strategies for assessing drug efficacy: (1) tympanocentesis and culture before and during therapy (bacteriologic efficacy), (2) tympanocentesis before therapy and assessment of clinical efficacy in bacterial acute otitis media, and (3) no tympanocentesis and assessment of clinical efficacy in clinical (total) acute otitis media. For a drug with a bacteriologic efficacy of 100%, calculated clinical efficacy was 93% for bacterial acute otitis media and 89% for clinical acute otitis media. For a drug with bacteriologic efficacy of 27%, a rate consistent with no antibacterial therapy, efficacy was 71% for bacterial acute otitis media and 74% for clinical acute otitis media. We conclude that if efficacy is measured by symptomatic response, drugs with excellent antibacterial activity will appear less efficacious than they really are and drugs with poor antibacterial activity will appear more efficacious than they really are. The predominant phenomenon is that drugs with poor antibacterial activity will appear to be clinically effective in the treatment of acute otitis media.

Bacterial polysaccharide immune globulin for prophylaxis of acute otitis media in high-risk children

We evaluated the prevention of recurrences of acute otitis media (AOM) by bacterial polysaccharide immune globulin (BPIG), a hyperimmune human immune globulin prepared by immunizing donors with bacterial polysaccharide vaccines. We used a randomized, stratified, double-blind, placebo-controlled design. Children < or = 24 months of age with 1 to 3 prior episodes of AOM received BPIG, 0.5 ml/kg, or saline placebo intramuscularly at entry and 30 days later. During the 120-day follow-up period, AOM was diagnosed by using clinical criteria and was confirmed with tympanocentesis and culture of the middle ear exudates. Eighty-eight episodes of AOM were observed in 76 patients who completed the study. The incidence of AOM during the entire 120-day study period was similar in BPIG and placebo recipients. Pneumococcal AOM was significantly less frequent in BPIG recipients (0.21 episode per patient) than in placebo recipients (0.45 episode per patient; p = 0.05). Time spent free of AOM was significantly prolonged in recipients of BPIG, in comparison with placebo recipients (51 vs 35 days; p = 0.034). This study demonstrated that circulating antibody, even without stimulation of specific local immunity, may prevent infection of the middle ear. The use of immune globulin preparations for longer periods or at a higher dosage might decrease the incidence of recurrent AOM in otitis-prone children, and deserves further evaluation.

Objective diagnosis of otitis media in early infancy by tympanometry and ipsilateral acoustic reflex thresholds

Otitis media in early infancy carries a high risk of recurrent otitis media and prolonged middle ear effusion. To fulfill the need for objective diagnostic methods in this age group, we investigated susceptance tympanograms and ipsilateral acoustic reflex thresholds in infants younger than 5 months of age. Tympanometry and acoustic reflex thresholds were performed with an otoadmittance meter using a 660 Hz probe tone. Tympanograms were interpreted using quantitative measures. These findings were compared with independent otoscopic diagnoses in 67 ears with middle ear effusion and 69 ears that were effusion free. Diagnoses were confirmed by tympanocentesis when clinically indicated. There was excellent agreement among otoscopy, peak tympanogram susceptance, and ipsilateral acoustic reflex thresholds (kappa 0.82 to 0.86, agreement 91% to 93%). We conclude that susceptance tympanograms and ipsilateral acoustic reflex thresholds are accurate diagnostic tests for otitis media in infants younger than 5 months of age.

Antibody persistence after primary measles-mumps-rubella vaccine and response to a second dose given at four to six vs. eleven to thirteen years.

BACKGROUND Since 1989 the American Academy of Pediatrics and the ACIP have recommended a second dose of measles-mumps-rubella vaccine (M-M-R-II) at either school entry or age 11 to 13 years. Unfortunately few studies are available to compare responses to vaccine at the two ages. We performed a prospective trial to determine the persistence of antibody to measles, mumps and rubella vaccination in two age groups and the response to a second dose given at either 4 to 6 or 11 to 13 years. METHODS Thirty-eight children 4 to 6 years old and 57 children 11 to 13 years old were given a second dose of M-M-R-II as they presented for yearly examinations. All had received the first dose at > or = 15 months of age. Measles and rubella antibody were measured by enzyme-linked immunosorbent assay (ELISA) and neutralizing antibody (NT) assay, and mumps antibody was measured by an ELISA method only. An IgM-ELISA antibody assay for measles was used in selected children. Prevaccination and 3- to 4-week post-vaccination sera were obtained. Measles ELISA, measles-neutralizing antibody (NT) and rubella-neutralizing antibody (NT) assays were performed in all children. Seventy-nine of the 95 children had sufficient sera for repeat measles tests, as well as mumps and rubella ELISA determinations. RESULTS Before the second dose ELISA seropositivity rates for measles and mumps were not significantly different between the two groups. Rubella ELISA seropositivity was 67% in 11- to 13-year-olds, compared with 90% in 4- to 6-year-olds (P < 0.01), suggestive of waning immunity. Rubella NT seropositivity was also lower in 11- to 13-year-olds than in 4- to 6-year-olds (63% vs. 100%, P < 0.01). After revaccination, 100% of the children become seropositive for all 3 antibodies. We performed measles IgM-ELISA testing on all 17 measles-seronegative children, as well as 15 seropositive children and 19 children who were 1 month postvaccination with the first M-M-R-II at 15 months. The purpose was to determine whether the seronegative children were primary or secondary failures. Five of the 17 children with undetectable pre-second dose antibody made IgM measles antibody after revaccination, suggesting that they were primary vaccine failures. CONCLUSIONS Because all children became seropositive after revaccination, the age of administration can be based on the convenience of vaccine scheduling. However, in view of the apparent decline in rubella antibodies at 11 to 13 years, future studies of rubella vaccination should address the issue of whether earlier boosting leads to greater susceptibility at the time of reproductive age.

Comparison of acellular and whole-cell pertussis-component diphtheria-tetanus-pertussis vaccines in infants

In a multicenter, double-blind, randomized, longitudinal study, 252 children received licensed Lederle diphtheria-tetanus toxoids and pertussis vaccine adsorbed (DTP) at 2, 4, and 6 months of age, and 245 children received a DTP vaccine with the Lederle/Takeda acellular pertussis component (APDT) at the same ages. Both groups of children received APDT vaccine at 18 months of age. After each of the first three immunizations, APDT vaccine recipients had fewer local and systemic reactions than did DTP vaccinees. Reactions after the 18-month APDT vaccination were minimal in severity regardless of the vaccine previously received. Antibody responses to lymphocytosis-promoting factor and agglutinogens were more pronounced in DTP recipients; however, APDT recipients had a better serologic response to filamentous hemagglutinin, and responses to the 69K protein were equivalent. This APDT vaccine produces fewer reactions than the standard whole-cell DTP vaccine. The protective significance of the serologic responses to the APDT vaccine is unknown, but the greater response to filamentous hemagglutinin and equivalent response to the 69K protein compared with those to DTP vaccine seem promising.

Cefixime compared with amoxicillin for treatment of acute otitis media

Cefixime was compared with amoxicillin for treatment of acute otitis media in a randomized trial. Results of tympanocentesis on day 3 to 5 of therapy were used as the major outcome. Total daily doses were 8 mg/kg of cefixime and 40 mg/kg of amoxicillin. One hundred twenty-six patients were randomly assigned to receive treatment; 64 cultures grew pathogens. Pathogens were eradicated from the middle ear after 3 to 5 days of therapy in 27 (79.4%) of 34 children given amoxicillin and 26 (86.7%) of 30 children given cefixime (p = 0.47). When Streptococcus pneumoniae cases were analyzed, bacteriologic cure occurred in 14 (93.3%) of 15 children given amoxicillin and 12 (75%) of 16 given cefixime (p = 0.333). When cases of Haemophilus influenzae infection were analyzed, significantly more cures occurred with cefixime (10/10, 100%) than amoxicillin (8/13, 62%) (p = 0.046). Pathogens associated with failure of amoxicillin therapy were H. influenzae (five cases, two beta-lactamase-positive), S. pneumoniae (one case), and Moraxella catarrhalis (one case, beta-lactamase-positive). The four failures with cefixime therapy were all in patients infected with S. pneumoniae. Rates of rash, diarrhea, and vomiting were the same in both groups and did not necessitate stopping therapy. We conclude the following: (1) Cefixime and amoxicillin were equivalent in overall clinical and bacteriologic efficacy for otitis media. (2) Cefixime was more efficacious than amoxicillin in treating H. influenzae otitis media and should be preferred when H. influenzae is the suspected etiologic agent. (3) Side effects of both drugs were mild and equivalent.

A randomized controlled trial of amoxicillin plus clavulanate compared with cefaclor for treatment of acute otitis media

We performed a randomized controlled trial of amoxicillin plus clavulanate versus cefaclor for treatment of acute otitis media. Total daily doses given in three divided doses were 40 mg/kg amoxicillin plus 10 mg/kg clavulanate, and 40 mg/kg cefaclor. Pathogens were eradicated from the middle ear exudate after 3 to 6 days of therapy in 35 (97%) of 36 patients given amoxicillin-clavulanate compared with 24 (75%) of 32 given cefaclor (P = 0.028). When analysis was restricted to patients with positive urine or serum drug assays during therapy, pathogens were eliminated in 33 (97%) of 34 patients given amoxicillin-clavulanate compared with 21 (75%) of 28 given cefaclor (P = 0.026). Bacterial isolates associated with bacteriologic failure of cefaclor therapy were Streptococcus pneumoniae (two patients), beta-lactamase-negative Haemophilus influenzae (four), and beta-lactamase-positive Branhamella catarrhalis (two). The single failure with amoxicillin-clavulanate therapy was associated with non-beta-lactamase-producing H. influenzae isolated from the middle ear exudate. We conclude that cefaclor is less efficacious than amoxicillin-clavulanate for the treatment of acute otitis media.

Large dosage amoxicillin/clavulanate, compared with azithromycin, for the treatment of bacterial acute otitis media in children.

Background: A large dosage pediatric formulation of amoxicillin/clavulanate with an improved pharmacokinetic/pharmacodynamic profile was developed to eradicate many penicillin-resistant strains of Streptococcus pneumoniae and Haemophilus influenzae (including β-lactamase-producing strains). Methods: This randomized, investigator-blinded, multicenter trial examined treatment of bacterial acute otitis media (AOM) in children 6–30 months of age with amoxicillin/clavulanate (90/6.4 mg/kg/d in 2 divided doses for 10 days) versus azithromycin (10 mg/kg for 1 day followed by 5 mg/kg/d for 4 days). Tympanocentesis was performed at entry for bacteriologic assessment, at the on-therapy visit (day 4–6) to determine bacterial eradication and at any time before the end-of-therapy visit (day 12–14) if the child was categorized as experiencing clinical failure. Clinical assessments were performed at the on-therapy, end-of-therapy and follow-up (day 21–25) visits. Results: We enrolled 730 children; AOM pathogens were isolated at baseline for 249 of the amoxicillin/clavulanate group and 245 of the azithromycin group. For children with AOM pathogens at baseline, clinical success rates at the end-of-therapy visit were 90.5% for amoxicillin/clavulanate versus 80.9% for azithromycin (P < 0.01), and those at the on-therapy and follow-up visits were 94.9% versus 88.0% and 80.3% versus 71.1%, respectively (all P < 0.05). At the on-therapy visit, pretherapy pathogens were eradicated for 94.2% of children receiving amoxicillin/clavulanate versus 70.3% of those receiving azithromycin (P < 0.001). Amoxicillin/clavulanate eradicated 96.0% of S. pneumoniae (92.0% of fully penicillin-resistant S. pneumoniae) and 89.7% of H. influenzae (85.7% [6 of 7 cases] of β-lactamase-positive H. influenzae). Corresponding rates for azithromycin were 80.4% (54.5%) for S. pneumoniae and 49.1% (100% [1 of 1 case]) for H. influenzae (all P < 0.01 for between-drug comparisons). Conclusion: Amoxicillin/clavulanate was clinically and bacteriologically more effective than azithromycin among children with bacterial AOM, including cases caused by penicillin-resistant S. pneumoniae and β-lactamase-positive H. influenzae.

A randomized controlled trial of cefaclor compared with trimethoprim-sulfamethoxazole for treatment of acute otitis media

We performed a randomized controlled trial of cefaclor administered twice daily compared with trimethoprim-sulfamethoxazole (TMP-SMZ) administered twice daily for the treatment of acute otitis media. Pathogens were eradicated from the middle ear exudate after 3 to 6 days of therapy in 35 of 37 (95%) patients given TMP-SMZ compared with 28 of 40 (70%) given cefaclor (P = 0.017). Haemophilus influenzae was eliminated in 13 of 14 (93%) patients given TMP-SMZ compared with 10 of 18 (56%) given cefaclor (P = 0.047). Clinical outcomes failed to distinguish between patients given TMP-SMZ or cefaclor. Symptoms improved despite persistent infection in 11 of 13 (85%) patients; middle-ear effusion persisted after therapy in 38 of 61 (62%) patients despite eradication of pathogens. We conclude that twice daily TMP-SMZ is more efficacious than twice daily cefaclor for the treatment of acute otitis media and that clinical outcomes may fail to detect differences between antibacterial agents in comparative drug trials in acute otitis media.

Macrolide resistance: an increasing concern for treatment failure in children.

Background. Antimicrobial treatment of pediatric respiratory tract infections has evolved during the past 30 years as a result of antimicrobial resistance. The focus of antimicrobial therapy in these conditions has shifted from penicillins to other agents because of the dramatic increase in antimicrobial resistance among common respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. It is important for clinicians to understand how resistance develops so that they can help prevent this phenomenon from occurring with other antimicrobials. Methods. This article reviews the published literature on resistance to macrolide antimicrobials among common pediatric respiratory tract pathogens and clinical and bacteriologic outcomes of infections with these pathogens. Results. Resistance among common pediatric respiratory tract pathogens to macrolides occurs through two main mechanisms, alteration of the target site and active efflux. Although resistance patterns vary by geographic region, the widespread use of macrolides has contributed to the emergence of both types of macrolide-resistant organisms. Conditions that favor the selection and proliferation of resistant strains include children with repeated, close contact who frequently receive antimicrobial treatment or prophylaxis, such as children who attend day care. Recent US surveillance data show that 20 to 30% of S. pneumoniae are resistant to macrolides, with approximately two-thirds of macrolide-resistant strains associated with an efflux mechanism and the remainder associated with a ribosomal methylase. Additionally, although less well-known, virtually all strains of H. influenzae have an intrinsic macrolide efflux pump. As resistance to macrolides has increased, clinical failures have resulted, and these agents are no longer considered appropriate for empiric first line antimicrobial therapy of acute otitis media and sinusitis unless patients are truly penicillin-allergic. Therefore, other antimicrobials are recommended for the empiric treatment of children with respiratory tract infections, including higher doses of amoxicillin and amoxicillin/clavulanate (90 mg/kg/day amoxicillin), cefuroxime axetil and intramuscular ceftriaxone. Conclusions. As resistance to macrolides increases and clinical failures in children become more common with this class of antimicrobials, judicious use of antimicrobials is needed. This includes limiting antimicrobial use for viral infections and using the most effective agents when antimicrobials are clinically indicated, such as higher doses of amoxicillin and amoxicillin/clavulanate. Application of these principles may prevent proliferation and further development of resistance.