Correlation of higher antibody levels to pneumococcal proteins with protection from pneumococcal acute otitis media but not protection from nasopharyngeal colonization in young children.

OBJECTIVES: We previously found that nasopharyngeal (NP) colonization by Streptococcus pneumoniae elicits mucosal antibody responses to three protein vaccine candidates: pneumococcal histidine triad protein D (PhtD), pneumococcal choline-binding protein A (PcpA), and detoxified pneumolysin (PlyD1). Here we sought to determine if mucosal antibody levels to the proteins correlated with protection from acute otitis media (AOM) and NP colonization. METHODS: A total of 228 NP samples were prospectively collected from 100 healthy infants at 6-24 months of age. Whenever children were diagnosed with AOM, middle ear fluids were collected to confirm the diagnosis by microbiological culture. NP mucosal IgG and IgA were quantified by ELISA. RESULTS: Higher NP mucosal antibody levels to S. pneumoniae proteins correlated with significantly decreased likelihood of developing AOM caused by S. pneumoniae during 3 to 12 months of subsequent prospective monitoring. Specifically, children who did not experience AOM (n=111samples) caused by S. pneumoniae had two- to five-fold higher mucosal IgG levels to PcpA (all p values <0.01), six- to eight-fold higher IgA to PhtD (all p values <0.05); two- to three-folder higher IgA to PcpA (all p values <0.05), and two- to three-fold higher IgA to PlyD1 (p 0.08, p 0.03 and p 0.08) compared with children who did experience AOM (n=18samples). No association between mucosal antibody levels to the three proteins and NP colonization with S. pneumoniae was found. CONCLUSION: Higher NP mucosal IgG levels to PcpA, and IgA to PhtD, PcpA and PlyD1 correlate with reduced risk of development of S. pneumoniae AOM infection but not with reduced risk of NP colonization in young children.

Poor memory B cell generation contributes to non-protective responses to DTaP vaccine antigens in otitis-prone children.

We recently identified a cohort of children with recurrent episodes of acute otitis media (AOM) who fail to generate protective antibody titres to otopathogens and several vaccine antigens. In this study we determined the antibody levels against DTaP vaccine antigens, diphtheria toxoid (DT), tetanus toxoid (TT) and acellular pertussis toxoid (PT) in sera from 15 stringently defined otitis-prone (sOP) children and 20 non-otitis-prone (NOP) children. We found significantly lower concentrations of immunoglobulin (Ig)G antibodies against vaccine antigens in the serum of sOP children compared to age-matched NOP children. To elucidate immunological cellular responses to the vaccines in these children, we investigated memory B cell responses to DTaP vaccination. We used fluorescently conjugated vaccine antigens to label antigen receptors on the surface of memory B cells and examined the frequency of antigen-specific CD19(+) CD27(+) memory B cells in the peripheral blood. sOP children showed a significantly lower percentage of antigen-specific CD19(+) CD27(+) memory B cells than NOP children. We also found a linear correlation between the frequencies of memory B cells and circulating IgG titres for DT, TT and PT proteins. To our knowledge, this is the first study to show significant differences in memory B cell responses to DTaP vaccine antigens and their correlation with the circulating antibodies in young children with recurrent AOM.

Higher levels of mucosal antibody to pneumococcal vaccine candidate proteins are associated with reduced acute otitis media caused by Streptococcus pneumoniae in young children.

Mucosal immunity has a crucial role in controlling human respiratory tract infections. This study characterizes the naturally acquired mucosal antibody levels to three Streptococcus pneumoniae (Spn) protein antigens, pneumococcal histidine triad protein D (PhtD), pneumococcal choline binding protein A (PcpA), and pneumolysin (Ply), and assesses the association of the mucosal antibody levels with occurrence of acute otitis media (AOM) caused by Spn. Both nasopharyngeal (NP) immunoglobulin G (IgG) and IgA levels to all three proteins slightly decreased in children from 6 to 9 months of age and then gradually increased through 24 months of age. Spn NP colonization was associated with higher mucosal antibody levels to all three proteins. However, children with Spn AOM had 5-8-fold lower IgG and 3-6-fold lower IgA levels to the three proteins than children without AOM but asymptomatically colonized with Spn. Antigen-specific antibody levels in the middle ear fluid (MEF) were correlated with antibody levels in the NP. Children with AOM caused by Spn had lower antibody levels in both the MEF and NP than children with AOM caused by other pathogens. These results indicate that higher naturally acquired mucosal antibody levels to PhtD, PcpA and Ply are associated with reduced AOM caused by Spn.

Divergent mucosal and systemic responses in children in response to acute otitis media.

Acute otitis media (AOM), induced by respiratory bacteria, is a significant cause of children seeking medical attention worldwide. Some children are highly prone to AOMs, suffering three to four recurrent infections per year (prone). We previously determined that this population of children could have diminished anti-bacterial immune responses in peripheral blood that could fail to limit bacterial colonization in the nasopharynx (NP). Here, we examined local NP and middle ear (ME) responses and compared them to peripheral blood to examine whether the mucosa responses were similar to the peripheral blood responses. Moreover, we examined differences in effector cytokine responses between these two populations in the NP, ME and blood compartments at the onset of an AOM caused by either Streptococcus pneumoniae or non-typeable Haemophilus influenzae. We found that plasma effector cytokines patterned antigen-recall responses of CD4 T cells, with lower responses detected in prone children. ME cytokine levels did not mirror blood, but were more similar to the NP. Interferon (IFN)-γ and interleukin (IL)-17 in the NP were similar in prone and non-prone children, while IL-2 production was higher in prone children. The immune responses diverged in the mucosal and blood compartments at the onset of a bacterial ME infection, thus highlighting differences between local and systemic immune responses that could co-ordinate anti-bacterial immune responses in young children.

Five-year prospective study of paediatric acute otitis media in Rochester, NY: modelling analysis of the risk of pneumococcal colonization in the nasopharynx and infection.

During a 5-year prospective study of nasopharyngeal (NP) colonization and acute otitis media (AOM) infections in children during the 7-valent pneumococcal conjugate vaccine (PCV) era (July 2006-June 2011) we studied risk factors for NP colonization and AOM. NP samples were collected at ages 6, 9, 12, 15, 18, 24, and 30 months during well-child visits. Additionally, NP and middle ear fluid (MEF) samples were collected at onset of every AOM episode. From 1825 visits (n = 464 children), 5301 NP and 570 MEF samples were collected and analysed for potential otopathogens. Daycare attendance, NP colonization by Moraxella catarrhalis, and siblings aged <5 years increased the risk of Streptococcus pneumoniae NP colonization. NP colonization with S. pneumoniae, M. catarrhalis, or Haemophilus influenzae and a family history of OM increased the risk of AOM. Risk factors that increase the risk of pneumococcal AOM will be important to reassess as we move into a new 13-valent PCV era, especially co-colonization with other potential otopathogens.

CD4 T cell memory and antibody responses directed against the pneumococcal histidine triad proteins PhtD and PhtE following nasopharyngeal colonization and immunization and their role in protection against pneumococcal colonization in mice.

The present study was undertaken to understand the role of vaccine candidates PhtD and PhtE in pneumococcal nasopharyngeal (NP) colonization, their ability to induce CD4 T cell memory and antibody responses following primary NP colonization, and their contribution to protection against secondary pneumococcal colonization in mice. The study was also aimed at understanding the potential of immunization with PhtD and PhtE in eliciting qualitative CD4 T cell memory responses and protection against pneumococcal NP colonization in mice. PhtD and PhtE isogenic mutants in a TIGR4 background (TIGR4 ΔPhtD and TIGR4 ΔPhtE) were constructed and found to have a significantly reduced colonization density over time in the nasopharynges of mice compared to those of mice colonized with wild-type TIGR4. Mice with primary colonization by wild-type TIGR4, TIGR4 ΔPhtD, or TIGR4 ΔPhtE were protected against secondary colonization by wild-type TIGR4; nonetheless, the clearance of secondary colonization was slower in mice with primary colonization by either TIGR4 ΔPhtD or TIGR4 ΔPhtE than in mice with primary colonization by wild-type TIGR4. Colonization was found to be an immunizing event for PhtD and PhtE antigens (antibody response); however, we failed to detect any antigen (PhtD or PhtE)-specific CD4 T cell responses in any of the colonized groups of mice. Intranasal immunization with either PhtD or PhtE protein generated robust serum antibody and CD4 Th1-biased immune memory and conferred protection against pneumococcal colonization in mice. We conclude that PhtD and PhtE show promise as components in next-generation pneumococcal vaccine formulations.

Functional deficits of pertussis-specific CD4+ T cells in infants compared to adults following DTaP vaccination.

Understanding the immune responses that explain why infants require multiple doses of pertussis vaccine to achieve protection against infection is a high priority. The objective of this study was to compare the function and phenotypes of antigen-specific CD4(+) T cells in adults (n=12), compared to infants (n=20), following vaccination with acellular pertussis (DTaP) vaccine. Peripheral blood mononuclear cells (PBMCs) were stimulated with pertussis toxoid (PT), pertactin (PRN) and filamentous haemagglutinin (FHA). Multi-parameter flow cytometry was used to delineate CD4(+) T cell populations and phenotypes producing interferon (IFN)-γ, interleukin (IL)-2, tumour necrosis factor (TNF)-α and IL-4. Based on surface CD69 expression, infants demonstrated activation of vaccine antigen-specific CD4(+) T cells similar to adults. However, among infants, Boolean combinations of gates suggested that type 1 (Th-1) CD4(+) T cell responses were confined largely to TNF-α(+) IL-2(+) IFN-γ(-) or TNF-α(+) IL-2(-) IFN-γ(-) . A significantly lower percentage of polyfunctional T helper type 1 (Th1) responses (TNF-α(+) IFN-γ(+) IL-2(+) ) and type 2 (Th2) responses (IL-4) were present in the infants compared to adults. Moreover, a significantly higher percentage of infants' functional CD4(+) T cells were restricted to CD45RA(-) CCR7(+) CD27(+) phenotype, consistent with early-stage differentiated pertussis-specific memory CD4(+) T cells. We show for the first time that DTaP vaccination-induced CD4(+) T cells in infants are functionally and phenotypically dissimilar from those of adults.

An adenoviral vector-based mucosal vaccine is effective in protection against botulism.

A replication-incompetent adenoviral vector encoding the heavy chain C-fragment (H(C)50) of botulinum neurotoxin type C (BoNT/C) was evaluated as a mucosal vaccine against botulism in a mouse model. Single intranasal inoculation of the adenoviral vector elicited a high level of H(C)50-specific IgG, IgG1 and IgG2a in sera and IgA in mucosal secretions as early as 2 weeks after vaccination. The antigen-specific serum antibodies were maintained at a high level at least until the 27th week. Immune sera showed high potency in neutralizing BoNT/C as indicated by in vitro toxin neutralization assay. The mice receiving single dose of 2 x 10(7) p.f.u. (plaque-forming unit) of adenoviral vector were completely protected against challenge with up to 10(4) x MLD(50) of BoNT/C. The protective immunity showed vaccine dose dependence from 10(5) to 2 x 10(7) p.f.u. of adenoviral vector. In addition, animals receiving single intranasal dose of 2 x 10(7) p.f.u. adenoviral vector could be protected against 100 x MLD(50) 27 weeks after vaccination. Animals with preexisting immunity to adenovirus could also be vaccinated intranasally and protected against lethal challenge with BoNT/C. These results suggest that the adenoviral vector is a highly effective gene-based mucosal vaccine against botulism.

Pharmacodynamic analysis and clinical trial of amoxicillin sprinkle administered once daily for 7 days compared to penicillin V potassium administered four times daily for 10 days in the treatment of tonsillopharyngitis due to Streptococcus pyogenes in children.

An a priori pharmacokinetic/pharmacodynamic (PK/PD) target of 40% daily time above the MIC (T >MIC; based on the MIC(90) of 0.06 microg/ml for Streptococcus pyogenes reported in the literature) was shown to be achievable in a phase 1 study of 23 children with a once-daily (QD) modified-release, multiparticulate formulation of amoxicillin (amoxicillin sprinkle). The daily T >MIC achieved with the QD amoxicillin sprinkle formulation was comparable to that achieved with a four-times-daily (QID) penicillin VK suspension. An investigator-blinded, randomized, parallel-group, multicenter study involving 579 children 6 months to 12 years old with acute streptococcal tonsillopharyngitis was then undertaken. Children were randomly assigned 1:1 to receive either the amoxicillin sprinkle (475 mg for ages 6 months to 4 years, 775 mg for ages 5 to 12 years) QD for 7 days or 10 mg/kg of body weight of penicillin VK QID for 10 days (up to the maximum dose of 250 mg QID). Unexpectedly, the rates of bacteriological eradication at the test of cure were 65.3% (132/202) for the amoxicillin sprinkle and 68.0% (132/194) for penicillin VK (95% confidence interval, -12.0% to 6.6%). Thus, neither antibiotic regimen met the minimum criterion of > or =85% eradication ordinarily required by the U.S. FDA for first-line treatment of tonsillopharyngitis due to S. pyogenes. The results of subgroup analyses across demographic characteristics and current infection characteristics and by age/weight categories were consistent with the primary-efficacy result. The clinical cure rates for amoxicillin sprinkle and penicillin VK were 86.1% (216/251) and 91.9% (204/222), respectively (95% confidence interval, -11.6% to -0.4%). The results of a post hoc PD analysis suggested that a requirement for 60% daily T >MIC(90) more accurately predicted the observed high failure rates for bacteriologic eradication with the amoxicillin sprinkle and penicillin VK suspension studied. Based on the association between longer treatment courses and maximal bacterial eradication rates reported in the literature, an alternative composite PK/PD target taking into consideration the duration of therapy, or total T >MIC, was considered and provides an alternative explanation for the observed failure rate of amoxicillin sprinkle.

Comparison of European and U.S. results for cephalosporin versus penicillin treatment of group A streptococcal tonsillopharyngitis.

The outcome of cephalosporin versus penicillin treatment of group A streptococcal tonsillopharyngitis may differ between Europe and the USA. In the present study, Medline, Embase, reference lists, and abstract searches were used to identify randomized, controlled trials of cephalosporin versus penicillin treatment of group A streptococcal (GAS) tonsillopharyngitis. The outcomes of interest were bacteriologic and clinical cure rates from investigations conducted in Europe versus those conducted in the USA. Forty-seven trials involving 11,426 patients were included in the meta-analyses. For the comparison of 10 days of treatment with cephalosporins versus 10 days of treatment with penicillin, there were ten European and 25 U.S. trials, all involving pediatric subjects. The overall odds ratio (OR) favored cephalosporins more strongly in bacteriologic cure rate in Europe (OR=4.27, p<0.00001) than in the USA (OR=2.70, p<0.00001). Studies of 4-5 days of cephalosporin treatment versus 10 days of penicillin treatment were also analyzed. For nine European trials, the OR significantly favored cephalosporins (OR=1.30, p=0.03) in bacteriologic cure rates, but not as strongly as in the USA, (OR=2.41, p<0.00001). When results for 4-5 days of cephalosporin treatment were divided into pediatric versus adult populations, the differences in bacteriologic eradication rates obtained with cephalosporins were more pronounced in children. The likelihood of bacteriologic and clinical failure of GAS tonsillopharyngitis treatment in both European and U.S. patients is significantly less if a 10-day course of oral cephalosporin is prescribed, and is at least similar, if not significantly less, with a 4- to 5-day course of oral cephalosporin compared with a 10-day course of oral penicillin.

Acute otitis media disease management.

A first step in management decisions regarding otitis media must focus on accurate diagnosis to distinguish normal from acute otitis media (AOM) from otitis media with effusion (OME) or a retracted tympanic membrane without middle ear effusion. There are several classification schemes for AOM that may impact management decisions: patients with acute, persistent, recurrent, or chronic AOM may have a different distribution of bacterial pathogens and a different likelihood of success from antimicrobial therapy. Patient age, prior treatment history and daycare attendance are other important variables. The natural history of AOM without antibiotic treatment is generally favorable; however, from the few studies available, this is difficult to quantitate because the diagnosis was infrequently confirmed by tympanocentesis leaving the possibility that many patients entered into these trials may not have had bacterial AOM. Antibiotic choices should reflect pharmacokinetic/pharmacodynamic data and clinical trial results demonstrating effectiveness in eradication of the most likely pathogens based on tympanocentesis sampling and antibiotic sensitivity testing. Thereafter, compliance factors such as formulation, dosing schedule and duration of treatment and accessibility factors such as availability and cost should be taken into account. The increasing prevalence of antibiotic resistance among AOM pathogens and the changing susceptibility profiles of these bacteria should be considered in antibiotic selection. Current best practice recommends amoxicillin for uncomplicated AOM; continuing or switching to an alternative antibiotic based on clinical response after 48 hours of therapy; and selection of second line antibiotics as first line choices when the patient has already been on an antibiotic within the previous month or is otitis prone. Preferred second-line agents frequently noted in various guidelines include amoxicillin/clavulanate, cefdinir, cefpodoxime, cefprozil, and cefuroxime. Three injections of ceftriaxone or gatifloxacin (when approved) or diagnostic/therapeutic tympanocentisis (when approved) become a third-line treatment option. No single antibiotic or management strategy is ideal for all patients.

Diagnostic accuracy of otitis media and tympanocentesis skills assessment among pediatricians.

The comparative study presented here evaluated pediatricians from Italy, Greece, South Africa, and a reference group in the USA to determine (i) their ability to accurately diagnose acute otitis media (AOM) and otitis media with effusion (OME) using otoscopy, (ii) their knowledge of antibiotics, and (iii) their technical competence in performing tympanocentesis. The participants included 66 pediatricians from Italy, 115 from Greece, 36 from South Africa and 2,190 from the USA (reference group). Each pediatrician viewed nine video-recorded otoscopic examinations of tympanic membranes, after which their ability to differentiate AOM, OME and normal was ascertained. Questions were posed regarding appropriate, pathogen-directed antibiotic selection for AOM. A mannequin model was used to assess the technical proficiency of each pediatrician in performing tympanocentesis. Results were recorded for each group as the mean percentage +/- standard deviation. The correct diagnosis was made by each group of pediatricians in the following frequencies: Italy, 54+/-27% (range, 18-94%); Greece, 36+/-12% (range, 23-56%); South Africa, 53+/-21% (range, 22-88%); and the USA, 51+/-11% (range, 29-72%). The difference between results from Greece and the US reference group was statistically significant ( P=0.002). Pediatricians from each group over-diagnosed AOM with the following frequencies: Italy, 18+/-19% (range, 2-49%); Greece, 34+/-13% (8-50%); South Africa, 23+/-14% (7-44%); and the US reference group, 26+/-19% (7-51%). Pediatricians correctly selected an antibiotic recommended for treatment of AOM caused by drug-resistant Streptococcus pneumoniae as follows: Italy, 89%; Greece, 77%; South Africa, 82%; and the USA, 80%. For treatment of beta-lactamase-producing Haemophilus influenzae, the results were: Italy, 90%; Greece, 70%; South Africa, 81%; and the USA, 77%. Tympanocentesis was optimally performed by >/=86% of all pediatricians. The results indicate that pediatricians may often misdiagnose OME as AOM, but they select appropriate antibiotics about 80% of the time and can be trained to accurately perform tympanocentesis.

Assessing diagnostic accuracy and tympanocentesis skills in the management of otitis media.

BACKGROUND: The distinction between acute suppurative otitis media (AOM) and otitis media with effusion (OME) is important for antibiotic treatment decisions. Tympanocentesis may be useful in the diagnosis of AOM in selected patients. OBJECTIVES: To assess physician accuracy in diagnosing AOM and OME from physical examination findings and technical competence in performing tympanocentesis. DESIGN AND SUBJECTS: Five hundred fourteen pediatricians and 188 otolaryngologists viewed 9 different videotaped pneumatic otoscopic examinations of tympanic membranes during a continuing medical education course. Diagnostic differentiation of AOM, OME, and a normal tympanic membrane was ascertained. An infant mannequin model was used to assess the technical proficiency of performing tympanocentesis on artificial tympanic membranes. RESULTS: Overall, the average correct diagnosis by pediatricians was 50% (range, 25%-73%) and by otolaryngologists was 73% (range, 48%-88%). Pediatricians and otolaryngologists correctly recognized the absence of normality 89% to 100% and 93% to 100% of the time, respectively, but overdiagnosed AOM in 7% to 53% (mean, 27%) and in 3% to 23% (mean, 10%) of examinations. Performance of tympanocentesis was optimally performed by 89% of otolaryngologists and by 83% of pediatricians. CONCLUSIONS: The use of video-presented examinations to assess diagnostic ability suggests that AOM and OME may be misdiagnosed often. Interactive continuing medical education courses with simulation technology may enhance skills and improve diagnostic accuracy and treatment paradigms.

Low baseline antibody level to diphtheria is associated with poor response to conjugated pneumococcal vaccine in adults.

Joining polysaccharide antigens to protein increases immunogenicity in infants. In older adults, using conjugation to protein carriers to improve the immune response to pneumococcal polysaccharide vaccine has thus far proved disappointing. Low immunity to the carrier protein in the elderly may explain the failure of conjugated vaccines to elicit a T-cell-dependent response. We immunized 49 older adults (ages 60-78) and 50 younger adults (ages 18-45) with either 23-valent pneumococcal polysaccharide (PS) vaccine or 5-valent CRM197-conjugated pneumococcal oligosaccharide. Sera obtained before and after vaccination were analyzed for antibody to pneumococcal serotypes 14 and 6B and diphtheria toxin by ELISA. Baseline diphtheria toxin antibody level was lower in older adults than in younger adults (0.31 and 0.88 IU/ml, respectively; p < 0.0001). Adults with higher diphtheria antibody level had a higher antibody level to PS type 6B after vaccination than those with lower diphtheria antibody level (9.9 vs. 3.5 microg/ml, respectively; p = 0.01). Antibody level to PS type 14 was higher, but differed by baseline anti-diphtheria antibody level only when the older group was evaluated alone. Low levels of antibody to diphtheria protein may explain some of the lower responses to conjugate pneumococcal vaccine in older adults.

Fifth vaccination with dipthteria, tetanus and acellular pertussis is beneficial in four- to six-year-olds.

OBJECTIVE: Diphtheria, tetanus and pertussis serum antibody titers were assessed before a fifth dose of diphtheria-tetanus-acellular pertussis (DTaP) or diphtheria-tetanus-whole cell pertussis (DTwP) vaccination at age 4 to 6 years. METHODS: Healthy children who had participated in a series of National Institutes of Health-sponsored trials assessing DTwP and DTaP vaccines provided prevaccination sera before a fifth dose of DTwP or DTaP. The trial design was prospective, randomized and double blind. Diphtheria, tetanus and pertussis antibody titers were measured by enzyme-linked immunosorbent assay. Pertussis results are expressed in enzyme-linked immunosorbent assay units/ml based on US Food and Drug Administration reference sera. Tetanus and diphtheria toxin concentrations are expressed in IU/ml with a WHO international reference sera as a standard. RESULTS: For diphtheria 100% of the children had antibody titers above the minimum protective level of 0.01 IU/ml and 86 to 100% (depending on prior vaccine product) had titers >0.1 IU/ml. However, only 0 to 40% of the children had antibody titers > or =1.0 IU/ml, a titer associated with more certain durable protection. For tetanus none of the children had an antibody titer below 0.01 IU/ml, and 93 to 100% had titers > or =0.1 IU/ml, a titer associated with more certain, durable protection. For pertussis the geometric mean concentrations of antibody before booster were uniformly very low, and the percentage of children exceeding the minimum detectable titer of antibody by 4-fold was also low. CONCLUSION: Before a 4- to 6-year-old booster, a large proportion of children have titers of antibody to diphtheria below the certain, durable protective level. Because serologic correlates and minimum protective titers of antibody to pertussis antigens have not been established, the relevance of the low titers determined in the current study is unknown but a potential concern.

Are follow-up throat cultures necessary when rapid antigen detection tests are negative for group A streptococci?

The frequency of obtaining false-negative Group A Streptococcal (GAS) rapid antigen detection (RAD) tests utilizing currently available kits in a private practice setting and the cost effectiveness of requiring follow-up throat cultures were studied. Laboratory records of the Elmwood Pediatric Group (EPG), Rochester, NY, were retrospectively reviewed to identify all patients with pharyngeal RAD tests for GAS performed from January 1996 through May 1999. From January 1996 through October 1997 (study period 1), EPG physicians used either a RAD test or a throat culture to identify GAS; from November 1997 through May 1999 (study period 2), RAD tests were used as the primary test on all patients. Rapid antigen detection test negative results were confirmed with culture. During the 3-year study 11,427 RAD tests were performed. 8,385 (73.4%) were negative and 3,042 (26.6%) were positive. In study period 1, 3,547 (73.2%) were negative and 1,299 (26.8%) were positive; in study period 2 4,837 (73.5%) were negative and 1,743 (26.5%) were positive. Of the 8,385 negative tests, 8,234 (98.2%) were followed up with throat cultures. Of these, 200 (2.4%) were identified to have been negative RAD tests that were throat culture positive (132 [3.8%] of 3,474 in study period 1 and 68 [1.4%] of 4,764 in study period 2). A cost analysis was performed for study period 2, which showed that abandoning throat culture confirmation would generate a cost saving of $13,521 per year to the practice. Throat culture confirmation of RAD test negative results in pharyngitis patients may not be medically necessary for most patients with currently available RAD tests and is costly.

A prospective observational study of 5-, 7-, and 10-day antibiotic treatment for acute otitis media.

OBJECTIVE: To compare 5-, 7- and 10-day duration of antibiotic therapy for acute otitis media (AOM) in children. STUDY DESIGN AND SETTING: Prospective nonrandomized 1-year evaluation of 3 treatment durations for AOM in a private pediatric setting. Outcomes assessed at 14 +/- 4 days after start of therapy with clinical response categorized as cure, improvement, or failure. RESULTS: A total of 2172 children were studied; 46.4% were < or =2-years-old. Antibiotics used were amoxicillin (61.9% of patients), trimethoprim/sulfamethoxazole (11.7%), cephalosporins (14.2%), amoxicillin/clavulanate (5.2%), and macrolides/azalides (4.8%). No overall difference in outcome was observed comparing the 5-day (n = 707), 7-day (n = 423), or 10-day (n = 1042) treatments, including children < or =2-years-old. However, in the subset who had an episode of AOM in the preceding month, outcome differed; 5-day treatment was followed by more frequent failure than 10-day treatment (P < 0.001). In logistic regression analysis, variables identified as contributing to a cure were: >2-years-old (P < 0.0001), no AOM in the preceding month (P = 0.07), or preceding 12 months (P = 0.03). CONCLUSIONS: Our study supports the transition from 10 to 5 days for standard AOM antibiotic treatment duration in most patients. A 10-day regimen may be superior in children who have experienced an episode of AOM within the preceding month, a known risk factor for resistant bacterial infection in the otitis-prone patient.

Assessing diagnostic accuracy and tympanocentesis skills by nurse practitioners in management of otitis media.

PURPOSE: To assess healthcare provider accuracy in recognizing the physical examination findings of acute otitis media (AOM) and otitis media with effusion (OME) and technical competence in performing tympanocentesis using a simulation model. DATA SOURCES: A descriptive study of 1,271 pediatricians and 206 nurse practitioners (NPs) who viewed 9 different video-recorded pneumatic otoscopic examinations of tympanic membranes (TMs) during a continuing medical education (CME) course. Diagnostic differentiation of AOM, OME and normal was ascertained. A mannequin model of a one-two year old child was used to assess technical proficiency of performing tympanocentesis on artificial tympanic membranes. CONCLUSIONS: Overall, the average correct diagnosis by all healthcare providers was 46% (range = 25% to 71%); by pediatricians it was 50% (25% to 71%) and by NPs 42% (25% to 68%). Pediatricians and NPs correctly recognized the absence of normality 86% to 99% and 68% to 99% of the time; they over-diagnosed AOM in 7% to 58% (average 27%) and 10% to 65% of examinations (average 31%), respectively. Performance of tympanocentesis was optimally performed by 73% of NPs. IMPLICATIONS FOR PRACTICE: The distinction between AOM and OME is important for antibiotic management decisions; tympanocentesis may be useful in diagnosis of AOM in selected patients. Healthcare providers may misdiagnose AOM and OME with some frequency. Nurse practitioners and pediatricians have the skills to be trained in the tympanocentesis procedure. Interactive CME courses with simulation technology may enhance skills and lead to a willingness to change and improve diagnostic accuracy and treatment paradigms.

Open-Label, parallel-group, multicenter, randomized study of cefprozil versus erythromycin in children with group A streptococcal pharyngitis/tonsillitis.

BACKGROUND: Cefprozil and erythromycin are acceptable alternatives to penicillin in the treatment of pharyngitis/tonsillitis due to group A beta-hemolytic streptococcus (GABHS). OBJECTIVE: The purpose of this trial was to determine the relative efficacy and tolerability of cefprozil and erythromycin in the treatment of pediatric pharyngitis/tonsillitis due to GABHS. METHODS: This trial compared the bacteriologic and clinical efficacy of erythromycin and cefprozil in children 2 to 12 years of age with culture-documented GABHS pharyngitis/ tonsillitis. Children who were allergic to penicillin, cefprozil, or erythromycin were excluded. Patients were prospectively randomly assigned to receive 10 days of oral therapy with either cefprozil suspension 15 mg/kg per day in 2 divided doses or erythromycin ethylsuccinate suspension 30 mg/kg per day in 3 divided doses. Primary efficacy end points were bacteriologic and clinical response 2 to 8 days after treatment ended. The frequency and severity of adverse events and their relationship to treatment were also assessed. RESULTS: A total of 199 patients were enrolled and treated (cefprozil, 99; erythromycin, 100); 12 patients in the cefprozil group and 15 in the erythromycin group were not evaluable. The GABHS eradication rate was significantly higher with cefprozil (95%) than with erythromycin (74%) (P = 0.001). The posttreatment carrier rate was lower in the cefprozil group (5%) than in the erythromycin group (18%) (95% CI, -22.3 to -3.8). Clinical cure rate was 90% (78/87) with cefprozil and 91% (77/85) with erythromycin (P = 0.95) (treatment group difference, -0.93; 95% CI, -9.9% to 8.0%). The overall incidence of drug-related adverse events was not significantly different in the 2 groups (11% with cef- prozil, 18% with erythromycin). The most common adverse events were diarrhea and vomiting. Two patients in the erythromycin group discontinued therapy because of adverse events. CONCLUSIONS: The bacteriologic eradication rate was significantly greater with cefprozil compared with erythromycin in children with pharyngitis/tonsillitis. Both cefprozil and erythromycin produced a clinical cure in >90% of patients.

Costs of illness due to Bordetella pertussis in families.

OBJECTIVE: To assess costs of pertussis morbidity among families in a community setting. DESIGN: Prospective survey. RESULTS: Sixty-nine families (87 individuals) were studied. Twelve of 14 families with household contacts included an ill adolescent or parent. This individual was the first identified pertussis case within the household in 8 families. A family member required an average of 1.6 visits before (range, 0-7 visits) and after (range, 0-9 visits) pertussis was diagnosed; children younger than 1 year needed 2.5 and 2 visits, respectively. Symptomatic improvement occurred after a mean of 31 days (range, 4-134 days) after pertussis diagnosis and full recovery after a mean of 66 days (range, 5-383 days). Adults experienced the longest recovery time (median, 93 days) compared with other age groups. The average medical costs for an infant, child, adolescent, and adult were $2822, $308, $254, and $181, respectively. Parents lost an average of 6 workdays (range, 1-35 days) to care for an ill child; for these parents, costs associated with work loss averaged $767 per family. An average of 1.7 and 0.7 lost workdays accrued to bring an ill child to a physician's office and the emergency department, respectively. A majority (58%) of parents working while family members were ill with pertussis reported decreased work productivity ranging from 25% to 99%. Work-related costs contributed more than 60% of the overall costs of pertussis. CONCLUSIONS: The adverse financial effect of pertussis on 69 families in Monroe County, New York, was $145,903 ($2115 per family) and supports the need for booster immunizations in adolescents and adults. Arch Fam Med. 2000;9:989-996