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.

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.

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.

Host factors and early therapeutic response in acute otitis media.

To evaluate the relationship between eradication of bacterial infection and clinical improvement in children with otitis media, we reviewed the clinical outcome of bacterial otitis media in patients enrolled in double-blind trials of antibacterial therapy from 1979 to 1988. Cultures of middle ear exudates showed the distribution of bacterial pathogens to be similar to that observed in other geographic areas. Two hundred ninety-three patients had otitis media caused by bacterial pathogens and underwent repeat tympanocentesis after 3 to 6 days of therapy. Bacteriologic success was demonstrated in 253 patients (86%); 40 patients (14%) had bacteriologic failure. Children who had bacteriologic failure were younger than those with bacteriologic success (median age 10.6 vs 18.5 months; p = 0.001); 38% of patients who had bacteriologic failure were black, compared with 18% of patients with bacteriologic success (p = 0.007). Gender, history of frequent otitis media, and presence of bilateral otitis media were not risk factors for bacteriologic failure. Clinical success was demonstrated in 261 patients (89%); 32 patients (11%) had clinical failure. Agreement between clinical and bacteriologic response was 86% (95% confidence interval: 81.6% to 89.6%). Ninety-three percent (236/253) of subjects whose infection was eliminated had clinical resolution, whereas 37% (15/40) of those with bacteriologic failure had persisting symptoms or signs of clinical failure. We conclude that failure to eliminate bacteria from the middle ear is often associated with persistent signs and symptoms. Bacteriologic failure affects children less than 18 months of age almost exclusively. Bacteriologic and clinical failure are frequently discordant; mechanisms unrelated to the bacterial infection may explain some of the persisting clinical signs.

Prevention of pneumococcal otitis media in chinchillas with human bacterial polysaccharide immune globulin.

Clinical and experimental observations suggest that immune globulin may prevent otitis media (OM) in children. We performed experiments in chinchillas to test the hypothesis that human bacterial polysaccharide immune globulin (BPIG) might prevent OM caused by Streptococcus pneumoniae. Animals were given BPIG or saline intraperitoneally on day 0. On day 3 the epitympanic bulla was inoculated with S. pneumoniae type 7F. All 12 saline-treated and none of 12 BPIG-treated animals developed pneumococcal OM by day 7 (P less than 0.0001). Bacteremia developed in 6 of 12 saline- and 0 of 12 BPIG-treated animals (P = 0.007). Death with pneumococcal OM occurred within 28 days in 5 of 12 saline- and 0 of 12 BPIG-injected animals (P = 0.02). A chinchilla-specific immunoassay was used to show that surviving saline-injected animals developed serum anticapsular antibody; BPIG-treated animals had no detectable response. At levels of anticapsular immunoglobulin G similar to those of human adults, BPIG given systemically prevented pneumococcal OM and disseminated infection in chinchillas. BPIG may be of value in preventing human bacterial infection and may also inhibit development of antibody if it affects local infection or colonization. Specific immunoglobulin G antibody may provide an important antibacterial defense of mucosal surfaces of the respiratory tract.

Live attenuated varicella vaccine in healthy 12- to 24-month-old children.

We studied live attenuated Oka/Merck varicella vaccine in 147 seronegative children 12 to 24 months of age and their 94 seronegative older siblings 2 to 12 years of age. The vaccine side effects were mild, consisting of a papular rash in 15 of 147 (10.2%) children 12 to 24 months and seven of 94 (7.4%) siblings. In a subset of 12- to 24-month-old children, modified fluorescent antibody test for membrane antigen was not detectable at seven days postimmunization but was detectable in 50% by 14 days and in 100% by 21 days. Within 6 weeks, 96.6% of children 12 to 24 months and 94.7% of siblings seroconverted. The geometric mean titer did not vary with age at immunization. One-year blood samples were obtained from 70 children 12 to 24 months of age who seroconverted; 92.9% retained detectable antibody. The geometric mean titer had decreased from 55.7 to 18.6. Of these 70 children, 34% had been exposed to varicella since immunization, and two cases of varicella were observed in seroconverters. Both cases were mild, with less than 50 vesicles. Oka/Merck varicella vaccine appears to be safe, highly immunogenic, and protective against 96% of exposures to natural varicella during the first year after vaccination in infants. Those cases of varicella that develop in immunized children appear substantially reduced in severity.

Early recurrences of otitis media: reinfection or relapse?

In a prospective study, 36 (35%) of 103 patients had early recurrence of acute otitis media. We wished to identify risk factors for early recurrences (those recurring within 1 month of initial diagnosis) and to determine if the second episode was caused by the same pathogen (relapse) or a new organism (reinfection). When the same bacterial species was recovered in both episodes, Streptococcus pneumoniae were serotyped and Haemophilus influenzae were classified by biotypes and by electrophoretic pattern of the outer membrane proteins. Twenty-nine patients underwent tympanocentesis at the time of the recurrent episode. In 13, no pathogen was recovered either initially or at the time of recurrence. Twelve (75%) of the remaining 16 patients had reinfection; only four (25%) had relapse. Thus, early recurrences of acute otitis media were more often caused by a new organism. This finding suggests that underlying susceptibility to middle ear infection is important in the development of recurrent otitis media. Pediatricians should not assume that early recurrences are necessarily the result of failure of initial treatment. Tympanocentesis may be helpful in this setting to aid in choosing appropriate antibiotic therapy.

Acute otitis media caused by Branhamella catarrhalis: biology and therapy.

Since 1980, we have observed an epidemic of otitis media caused by Branhamella catarrhalis. This event was characterized by studying the nasopharyngeal colonization of infants and children with B. catarrhalis and the clinical presentation and therapeutic outcome of acute otitis media caused by this organism. Pharyngeal colonization with B. catarrhalis was commoner in winter than summer. B. catarrhalis was present in middle-ear fluid (MEF) of 17% of children with otitis media, and was commoner in fall and winter (20%) than in spring and summer (11%, P less than .05). Seventy-five percent of isolates produced beta-lactamase (Ravasio type). In five of 20 patients, treatment with beta-lactamase-susceptible agents failed to sterilize B. catarrhalis-infected MEF. All of these five patients were infected with beta-lactamase-producing strains. The increasing prominence of antibiotic-resistant B. catarrhalis in acute otitis media may lead to a reevaluation of initial antibiotic therapy for acute otitis media, particularly in winter or in areas where colonization with such strains is prevalent.

Renal ultrasound evaluation of urinary tract infections in children.

Ultrasonography of the kidney may replace the intravenous pyelogram as the study of choice in identifying treatable abnormalities in children with urinary tract infection. In a series of 64 consecutive children with urinary tract infection in whom an intravenous pyelogram, renal ultrasound, and voiding cystogram were performed, only one treatable abnormality (calyceal dilation) was identified by intravenous pyelogram, and it was not detected by ultrasound. Eleven children showed vesicoureteral reflux on the cystogram. In an additional 43 children in whom intravenous pyelogram was done only if the ultrasound or cystogram were abnormal, there were five abnormal cystograms. Four treatable abnormalities were identified by ultrasound, and there were confirmed by the intravenous pyelogram. Ultrasound should replace the intravenous pyelogram in children with a normal cystogram because of its accuracy, safety, and high patient acceptance. We have also documented a significant volume increase with acute infection in one or both kidney(s) of those children having upper urinary tract infection. Fifteen of 18 children with upper urinary tract infection had volume increases of 30% or more in at least one kidney; whereas only four of 21 children with lower urinary tract infection had increases of greater than 30% (P less than .005). Ultrasound volume measurements provide a new, noninvasive method for identifying the probable site of urinary tract infection.

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.

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.

Therapy of acute otitis media caused by Branhamella catarrhalis. Preliminary report.

Since 1980, we have observed an increased incidence of otitis media caused by Branhamella catarrhalis. The outcome of therapy of acute otitis media caused by this organism has been studied in a number of randomised clinical trials. 75% of isolates produced beta-lactamase. Failure to sterilise B. catarrhalis-infected middle ear exudates occurred in 3 of 11 patients treated with amoxycillin or bacampicillin, 2 of 19 treated with cefaclor, but in no patients treated with co-trimoxazole (n = 10) or amoxycillin-clavulanic acid (Augmentin), [n = 9]. All treatment failures were associated with beta-lactamase-producing strains of B. catarrhalis. The emergence of antibiotic-resistant strains of B. catarrhalis in acute otitis media indicates the need for a re-evaluation of initial antibiotic therapy of this infection. This may be particularly true for areas where there is a high incidence of strains which elaborate beta-lactamase.

Isoelectric focusing of beta-lactamases from sputum and middle ear isolates of Branhamella catarrhalis recovered in the United States.

Branhamella catarrhalis obtained from the sputum of 146 patients with lower respiratory tract disease and from middle ear fluids of 26 children with otitis media were evaluated for beta-lactamase activity and the enzymes were characterised by isoelectric focusing (IEF). 71% (103 of 146) of the sputum isolates and 77% (20 of 26) of the ear isolates produced beta-lactamase. By IEF, the beta-lactamases of 113 of 123 (92%) strains revealed patterns identical with the Ravasio type strain, having unique enzyme bands at pIs of 6.4 and 6.65. The remaining 10 isolates (8%) produced patterns similar to the 1908 type strain with a unique band of activity having a pI of 6.55. In addition, the 1908 types revealed a band of minor enzyme activity with a pI of 7.55 that was absent from the Ravasio types. All strains tested shared major enzyme bands with pIs of 5.1, 5.3, 5.55 and 6.1. These results indicate that the most common beta-lactamase(s) produced by clinical isolates of B. catarrhalis in the United States are similar to those produced by the Belgian Ravasio type strain.

Identification of children requiring radiologic evaluation for urinary infection.

Sixty-nine children younger than 13 years of age with urinary tract infection were evaluated to identify risk factors for treatable urologic problems; i.e. those requiring surgery or prolonged antibiotic prophylaxis. All children had a renal ultrasound, intravenous pyelogram and voiding cystogram performed 4 to 6 weeks after the infection. Eleven children with treatable problems were identified, 10 with vesicoureteral reflux and 1 with a ureterocele. For identification of treatable problems the predictive value of a positive test was: (1) fever, 10 of 24 (41.7%); (2) abnormal D-deaminoarginine vasopressin renal concentrating ability, 8 of 24 (33.3%); (3) serum C-reactive protein greater than or equal to 1.0, 8 of 25 (32.0%); (4) Elevated urine N-acetylglucosaminidase, 5 of 16 (31.2%); (5) erythrocyte sedimentation rate greater than or equal to 25, 6 of 21 (28.6%); and (6) age less than 5 years, 10 of 43 (23.3%). Absence of fever denotes a low risk (less than 3%) of finding a treatable problem. Afebrile girls older than 5 years of age can have radiologic evaluation deferred until infection recurs. The presence of fever indicates a high risk of treatable urologic problems (41.7%) and warrants complete radiologic evaluation with the first urinary infection.

Ipsilateral and contralateral acoustic reflexes in neonates.

Ipsilateral and contralateral acoustic reflexes were studied in neonates using 220 and 660 Hz probe tones and 500, 1000, 2000, and 4000 Hz activators. Activator sound pressure level was measured in all ears. Ipsilateral and contralateral reflexes were detected three times more frequently with a 660 Hz probe tone than with a 220 Hz probe tone. The maximum detection rate (76%) occurred with 1000 and 2000 Hz ipsilateral activators and the 660 probe tone. There was no significant difference between neonatal and adult ipsilateral thresholds at 500, 1000, and 4000 Hz. Neonatal intrameatal sound pressure levels for ipsilateral activators were found to be significantly higher than would be indicated from the otoadmittance meter manufacturer's specifications.

Bacterial etiology of conjunctivitis-otitis media syndrome.

Simultaneous cultures of conjunctivae and middle ear exudates were obtained from 20 episodes of the syndrome of purulent conjunctivitis and otitis media. Paired cultures from 18 episodes yielded Haemophilus influenzae at both sites. In two cases with prior topical antibacterial therapy of the conjunctivitis, H influenzae was isolated from the middle ear exudate only. Biotyping and outer membrane protein analysis of H influenzae isolates from five patients demonstrated that: conjunctival and middle ear strains were concordant in all cases, and all five patients had different strains. The conjunctivitis-otitis media syndrome is most often caused by strains of nontypable H influenzae of diverse clonotype.