CLINICIAN INTERVIEW ACUTE OTITIS MEDIA IN THE ERA OF PCV-7. Interview with Stanley L. Block, Jr, MD, FAAP

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1 ACUTE OTITIS MEDIA IN THE ERA OF PCV-7 Interview with Stanley L. Block, Jr, MD, FAAP Dr Block is president of Kentucky Pediatric Research and has practiced full-time primary care pediatrics in rural Bardstown, Ky, for the past 22 years. He has been board recertified twice and holds appointments as Clinical Professor of Pediatrics at the University of Louisville and the University of Kentucky. Dr Block received his Doctor of Medicine degree from the University of Kentucky and completed his postgraduate work in pediatrics at Wake Forest University School of Medicine. For significant contributions to pediatric medicine, Dr Block has been awarded the 1998 Researcher of the Year in Pediatric Private Practice by the American Academy of Pediatrics; the 2001 Charles Bluestone Award by the American Society of Pediatric Otolaryngology; the 2002 and 2003 Burtis Burr Breese Award by the Pediatric Infectious Disease Society; and the 2004 Distinguished Alumnus Award by the University of Kentucky Medical School. Kentucky Pediatric Research is one of the largest pediatric ambulatory research groups in the United States, participating in more than 250 clinical trials. Dr Block is a reviewer for several publications, including the Pediatric Infectious Disease Journal, Pediatrics, Southern Medical Journal, the Journal of Pediatrics, and Pediatric Drugs. He serves as a writer and editorial board advisor for the Pediatric Infectious Disease Journal, Infectious Diseases in Children, and Pediatric Annals, as well as the quarterly Pediatric Infections Forum. He is the co-chief editor for and an advisory board member of the National Campaign for Influenza Prevention and an advisory board member of the National Alliance for Advancement of ADHD Care. Dr Block is a recognized opinion leader on infectious diseases in ambulatory pediatrics, having published, as first author or co-author, more than 130 original papers, review articles, and abstracts on acute otitis media (AOM), vaccines, microbiology, antibiotic resistance in pediatrics, and attention-deficit/hyperactivity disorder. He was first author of landmark papers describing the role of penicillin-resistant pneumococcus in AOM, Chlamydia pneumoniae in AOM, and C pneumoniae and Mycoplasma pneumoniae in community-acquired pneumonia in children. He has presented clinical data at annual meetings of the American Academy of Pediatrics, the Society for Pediatric Research, and the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), and at pediatric grand rounds across the United States, Canada, and Europe. In the following interview with Advanced Studies in Medicine (ASiM), Dr Block discusses what impact immunization of the pediatric population with 7-valent pneumococcal conjugate vaccine (PCV-7) will have on AOM. ASiM: How important are the third dose and the booster dose of PCV-7 for full protection against vaccine serotypes? Dr Block: The first 3 doses of PCV-7 have a major impact on invasive disease. For most children, the peak occurrence of AOM is between 6 and 18 to 24 months of age. 1,2 Consequently, optimizing protection against mucosal disease such as AOM after 12 months is very important. Prelicensure evaluation of PCV-7 in infants within Kaiser Permanente found that more than 97% of recipients of PCV-7 Advanced Studies in Medicine S937

2 achieved 0.15 mg/ml or greater anticapsular antibody for all serotypes after the primary series of 3 doses, which correlates with the observed protective efficacy for invasive disease of 97.3%. The children were randomized by a ratio of 1:1 to receive PCV-7 or control vaccine at 2, 4, 6, and 12 to 15 months of age. 3 However, the data for children who received the third dose late or not at all suggest that protection against mucosal disease did not last to 12 months of age without the third dose. 4 Additionally, PCV-7 was most effective shortly after the booster dose (ie, during ages 15 to 18 months) when vaccinated children had 12.2% fewer otitis visits than control children (95% confidence interval, 8.2 to 16.0). 4 Thus, the available immunologic data suggests that the booster dose after 12 months of age is an important facet of protection against mucosal disease, 4 whereas 2 or 3 doses are probably sufficient to protect most children against invasive disease. 5 ASiM: Your participation in multiple clinical trials of PCV-7 has enabled you to immunize 94% of your pediatric patients with PCV-7 since What changes in the rate of upper respiratory tract infections have you seen in your pediatric population now that the majority has received at least 2 to 3 doses of PCV-7? Dr Block: We have seen an impact far exceeding previous expectations of PCV-7 on rates of both AOM and sinusitis, and also on the number of total antibiotic days. We compared annual rates of AOM, sinusitis, and antibiotic use during the first 3 years of life in a cohort of 274 children consecutively born from 1993 through 1994 (pre PCV-7) with a cohort of 221 children consecutively born from 2000 through 2001, 94% of whom received 3 or 4 doses of PCV-7. 6 Both cohorts of children were 91% white, and nearly half were enrolled in day care. The mean number of AOM episodes during the first 3 years of life was reduced by 19% in the PCV-7 cohort compared with the pre PCV-7 cohort. Surprisingly, the biggest impact was actually in year 3, when there was a 29% reduction. 6 With regard to rates of sinusitis, there was an impressive 59% reduction (range 39%-69% annually) in the first 3 years of life in the PCV-7 cohort compared with the pre PCV-7 cohort (Block SL, unpublished data, 2004). ASiM: Has the influence of herd immunity in your study exceeded previous predictions of protection of AOM? Dr Block: Herd immunity is the indirect protection from infection of susceptible members of a population brought about by the presence of immune individuals. Along with the profound shift in AOM microbiology with the advent of PCV-7, we have also seen a much greater impact on overall AOM rates than the modest 6% to 9% drop suggested by premarket studies. Before PCV-7, we did about 100 to 125 ear taps a year for kids with more than 2 treatment failures. Now it is 25 to 35, tops. We are just not seeing severe AOM anymore. I attribute this impact largely to herd immunity, which explains why it was not seen in earlier studies. They were done in small segments of their respective populations, in contrast to our community where almost all children have been vaccinated. So, we have seen notable herd immunity occurring on rates of AOM and sinusitis in the relatively closed population within our area when rates of uptake and availability of PCV-7 are high. Some critics say these findings are the result of the more stringent diagnostic criteria for pediatric AOM and acute bacterial rhinosinusitis (ABRS) that have been developed and propagated by public health officials over the past decade. Yet, these criteria likely had no impact on our results. All of the pediatricians were experienced otoscopists who have performed tympanocentesis for routine care and clinical research, 7 and our clinicians were already using defined parameters confirmed by clinical examination. Our diagnostic accuracy for AOM has been corroborated in multiple clinical trials using tympanometry, acoustic reflectometry, and/or especially tympanocentesis. Indeed, our diagnostic criteria for pediatric AOM and ABRS have remained consistent for the last 12 years. Therefore, the changes in rates of infection that we observed were strictly related to the introduction of PCV-7. But this also means that for practices using poor examination technique, looser diagnostic criteria, looser prescriptive pens, or disposable speculums and otoscopes with alkaline batteries, the reduction on rates of AOM and sinusitis likely will be much less perceptible. ASiM: With regard to the etiology of AOM, have you seen changes in the rates of recovery of the predominant pathogens? Dr Block: I think a historical perspective will help S938 Vol. 4 (10E) December 2004

3 us understand this issue. Approximately cases of invasive Haemophilus influenzae occurred in the United States in the early 1980s. In 1985, the first H influenzae type B (Hib) vaccine was introduced followed by a conjugate Hib vaccine in The widespread use of these vaccines has resulted in a greater than 99% decline in invasive disease compared with the early 1980s. This dramatic decline in invasive H influenzae disease was an impressive public health benefit but it also altered the bacterial etiology of AOM. As H influenzae decreased, Streptococcus pneumoniae became the more prevalent cause of bacterial AOM. Now that a conjugate pneumococcal vaccine has been mandated in children, it is not unexpected that the use of PCV-7 has also had a major impact on the prevalence of the key AOM pathogens. Among children aged 7 to 24 months with severe and/or refractory AOM, we compared 336 AOM isolates obtained from 1992 to 1998 (pre PCV-7) with 83 AOM isolates obtained from 2000 to 2003 from children who had received 3 or 4 doses of PCV-7. 2 The rate of gram-negative pathogens increased from 50% to 66% (P <.001). Nontypeable H influenzae increased from 41% to 56% (P =.01). 2 Among gram-negative AOM isolates, the overall rate of beta-lactamase producing organisms increased from 32% to 47% (P =.007) 2 showing that beta-lactamase producing gram-negative organisms are responsible for about half of all middle ear isolates. Among PCV-7 vaccinated children who had recurrent AOM (defined as an episode of AOM within 7 to 28 days of the last dose of antibiotic), we found that 72% of cases were due to H influenzae rather than drug-resistant pneumococcus. 2 In fact, the proportion of pneumococcal pathogens has declined significantly from 48% pre PCV-7 to 31% post PCV-7 (P =.007). We have also seen a moderate decrease in the rate of penicillin-nonsusceptible pneumococci from 25% to 19%; however, this decrease is not statistically significant. 2 Casey and Pichichero reported similar findings among children in Rochester, NY, with recurrent or persistent AOM (defined as nonresponders after 1 or 2 empiric antibiotic courses or failures after 48 hours on treatment) who had received PCV-7. 8 The authors found that 65% of recovered organisms during the period 2001 to 2003 were gram negative, 57% were H influenzae, and 55% were beta-lactamase positive H influenzae. So, I surmise that these microbiologic changes are probably occurring across the United States. 8 ASiM: What are the implications of the changing microbiology for future treatment of AOM as young children approach universal rates of PCV-7 vaccination with at least 3 doses? Dr Block: Once the vaccine supply is adequate, I believe we will continue to see a decline in the overall proportion of pneumococcal pathogens in AOM. We are now entering a gram-negative era for AOM. For coverage of both gram-negative pathogens and the residual penicillin-susceptible and intermediately resistant pneumococci, the third-generation cephalosporins and amoxicillin/clavulanate demonstrate excellent in vitro susceptibility and in vivo clinical efficacy in children with AOM. Amoxicillin/clavulanate has been accepted as the gold standard of treatment by the American Academy of Pediatrics/American Academy of Family Physicians (AAP/AAFP). 9 It is a very good drug for gram-negative pathogens as well as most strains of pneumococci. But with the emergence of H influenzae as the major pathogen in AOM and the increase in beta-lactamase producing organisms, certain thirdgeneration cephalosporins should be included in any armamentarium for the treatment of AOM as these agents also have excellent activity and cause less gastrointestinal disturbance. Among the third-generation oral cephalosporins, cefdinir, cefpodoxime, cefixime, and ceftibuten are available for the treatment of AOM. 10 Of the available third-generation cephalosporins, cefdinir and cefpodoxime have a distinct advantage in terms of both intermediate penicillin-nonsusceptible S pneumoniae and gram-negative coverage. 11,12 Cefixime provides limited pneumococcal coverage. 12 Ceftibuten does not provide coverage of pneumococcus or Moraxella catarrhalis, 13 and therefore should not be used in pediatric patients for AOM. Despite the coverage it provides, a real limitation of cefpodoxime oral suspension is that it receives low ratings for taste and aftertaste. 14 In contrast, cefdinir oral suspension receives high ratings for taste and aftertaste when compared with cefpodoxime or cefuroxime. 14 Both cefpodoxime and cefdinir can be administered once daily for 10 days or twice daily for 5 days. 10 These benefits of better taste and flexible dosing may help to improve patient adherence leading to better patient outcomes. Advanced Studies in Medicine S939

4 ASiM: How does the clinical efficacy of standarddose amoxicillin/clavulanate compare with that of the third-generation cephalosporins in the treatment of children with AOM? Dr Block: We conducted an investigator-blinded clinical trial comparing 5 days of cefdinir (14 mg/kg) given twice daily versus 10 days of amoxicillin/clavulanate (45 mg/kg of amoxicillin component) given twice daily. 15 We used low-dose amoxicillin/clavulanate in this study because the high-dose formulation was approved only 2 to 3 months before we began enrolling patients, and our study protocol had already undergone laborious revisions and approval by institutional review boards. This was a nontympanocentesis study that used clinical endpoints, and the diagnostic criteria for AOM were definitely adequate. In fact, our diagnostic criteria were more comprehensive than those in the AAP/AAFP guidelines because clinical signs/symptoms of otalgia, ear fullness, decreased hearing, or purulent discharge due to acute perforation of the tympanic membrane had to be associated with the presence in at least one ear of a minimum of 2 of the following: a bulging tympanic membrane, loss of the normal light reflex and tympanic membrane landmarks, and abnormal tympanic membrane mobility. Middle ear effusion was corroborated in all patients by acoustic reflectometry. 15 Based on data from experienced otoscopists using optimal culture technique for tympanocentesis, a pathogen should be present in 87% to 95% of cultures from an ear meeting these criteria In this particular study, the mean age of the children was 2.8 (±1.8) years, and 64% had received from 1 to 4 doses of PCV Overall, clinical response rates at the end-of-therapy visit (2-4 days post-therapy for either regimen) were equivalent between the 2 drugs (88% for cefdinir and 85% for amoxicillin/clavulanate). 15 However, among the subset of children who had ever received PCV-7, there was a statistically significant difference in efficacy favoring cefdinir over amoxicillin/clavulanate (92% vs 82%, P =.024; 95% confidence interval, 1.1 to 18.4). 15 When we looked specifically at children aged 6 to 24 months, in whom the occurrence of AOM is greatest, the impact of PCV-7 on drug efficacy was even more profound. Clinical cure rates were 92% for cefdinir compared with 77% for amoxicillin/clavulanate, with a P value of.019 when stratified by age. 15 The 95% confidence intervals were within 15% (3.5, 26.2), which is somewhat greater than the 10% that we would like to see. Our data indicate that cefdinir given twice a day for 5 days was very effective in children who had nonrefractory AOM, particularly among PCV-7 recipients. ASiM: Will high-dose amoxicillin remain an appropriate first-line therapy for AOM in children who are fully immunized with PCV-7? Dr Block: Although we may want to consider an antibiotic that provides better gram-negative coverage for initial therapy in children who have received PCV- 7, remember that our data and that from Casey and Pichichero were comprised mostly of children with recurrent or persistent AOM. 8 I believe high-dose amoxicillin should still remain first-line therapy for AOM. Amoxicillin is fairly inexpensive, extremely safe, modestly effective, and will cover a fair amount of pneumococcus and beta-lactamase negative strains of H influenzae. The use of this narrower-spectrum drug will help prevent the overuse of the more potent antibiotics in the all-too-often cases of diagnostic uncertainty, overdiagnosis, busy practitioners, and prescriptive pens susceptible to frequent parental pressure. Because the overall clinical efficacy of high-dose amoxicillin is reasonable and because infections with H influenzae and M catarrhalis may be less severe and often resolve without treatment, 19 at least initially with a tympanocentesis, high-dose amoxicillin is still an appropriate choice. ASiM: Will the changes in AOM microbiology in the PCV-7 era affect treatment choices for children who fail an initial course of therapy? Dr Block: When one looks at the sum total of the data, it looks like either amoxicillin/clavulanate or cefdinir should be the agent of choice when a child fails first-line therapy with amoxicillin. Both drugs have advantages and disadvantages. Amoxicillin/clavulanate probably has slightly better pneumococcal coverage, especially for penicillin-resistant pneumococcus. However, data from our practice and Casey s suggest that there has been a reduction in high-level resistance of pneumococci to penicillin since the introduction of PCV-7. 5 Among children 7 to 24 months of age, the choice between these agents is probably a flip of the coin. Cefdinir has some real advantages in terms of superior palatability and the fact that it can be administered once daily rather than twice daily for 10 days. These important benefits may help improve patient adher- S940 Vol. 4 (10E) December 2004

5 ence thereby improving the chances that a full course of therapy will be completed. Yet, for the clinician who sees patients daily, the AAP/AAFP guidelines indicate that amoxicillin/clavulanate is the only drug of choice for de novo AOM with fever or moderate to severe otalgia and for uncomplicated AOM that has failed to respond to initial antibiotic therapy. 9 But for the penicillin-allergic child or one who presents with vomiting, diarrhea, or an upset stomach, cefdinir would be the more appropriate choice. I believe it may be unwise to treat a child who has a fever and is not drinking or not eating well with amoxicillin/ clavulanate. If amoxicillin/clavulanate is not taken with substantial food or milk, it will commonly precipitate gastrointestinal distress. ASiM: Compared with standard-dose amoxicillin/clavulanate given twice daily for 10 days, would you expect adherence to be better with cefdinir given twice daily for 5 days and, if so, why? Dr Block: Yes, I would expect adherence to be better with the 5-day cefdinir regimen. Any time that duration of the dosing can be shortened, adherence can be improved. As for efficacy, I would recommend that for cefdinir, most clinicians should use a 10-day once-daily regimen for children younger than 2 years and for those who are treatment failures. Clinical trial experience with cefdinir and amoxicillin/clavulanate suggests that a standard 10-day course of therapy is preferable in younger children with AOM. 20,21 The 5- day twice-daily cefdinir regimen probably should be used only in children older than 2 years or in those with recurrent AOM who have not received antibiotics for at least a few weeks. ASiM: Could you comment on what some colleagues believe are limitations of this study; namely, the fact that you used standard-dose amoxicillin/clavulanate and did not do tympanocentesis? Dr Block: Those are the 2 biggest caveats to the data. With regard to the fact that we did not do tympanocentesis, some believe that clinical endpoints are not reliable as far as differentiating efficacy between drugs. However, there have been other clinical trials such as ours in which the evaluation of drug efficacy using clinical endpoints, rather than tympanocentesis plus cultures of middle ear fluid (MEF), clearly demonstrated between-treatment differences. This study showed a statistically significant difference between amoxicillin/clavulanate and cefdinir in children who had ever received PCV-7, with good P values and confidence intervals of 1.1 to As for the standard-dose of amoxicillin/clavulanate, children enrolled in the study were not otitis-prone and had not failed prior antibiotic therapy for AOM, the clinical setting in which high-dose amoxicillin/clavulanate should primarily be used at present. Another caveat to the data is that the mean age of 2.8 years for our patient population was a bit high. Ideally, in an AOM trial most of the children should be younger than 2 years because they are the hardest to treat and they tend to have the most failures. 22 ASiM: How would you differentiate some of the available cephalosporins? Dr Block: Let us compare cefdinir with cefprozil, both of which are commonly used cephalosporins. Cefprozil provides mainly gram-positive coverage, especially against pneumococcus, including penicillin intermediate-resistant strains. However, cefprozil provides minimal coverage for beta-lactamase negative or positive strains of H influenzae. The time above the MIC 90 (minimal inhibitory concentration) for this pathogen is only 21% of the dosage interval, 23 less than half that reported for cefpodoxime and, presumably, cefdinir. In addition, cefprozil has minimal activity against M catarrhalis; the MIC 90 is 8 mg/ml compared to that of 0.25 mg/ml for cefdinir. 13 Therefore, in the era of PCV-7 where two thirds of the pathogens are gram-negative, cefprozil probably does not have a major role and may not be better than placebo in terms of efficacy. Azithromycin, on the other hand, has some issues in terms of H influenzae coverage. Although azithromycin achieves concentrations in MEF that are consistently much higher than those in serum, it is believed by some to be tightly bound to the leckocytes. Two recent double tympanocentesis trials in children with uncomplicated AOM found that the standard azithromycin regimen (10 mg/kg on day 1, then 5 mg/kg on days 2 through 5) failed to eradicate H influenzae from MEF obtained on treatment days 3 to 6 in at least half of the patients (87% vs 39%, P =.0001). 24 The investigators suggest that the susceptibility breakpoints for H influenzae should be much lower Advanced Studies in Medicine S941

6 than at present for azithromycin. This would be consistent with the recent interpretation of Jacobs of susceptibility data for oral antibiotics using PK/PD (pharmacokinetic/pharmacodynamic) parameters. 25 Using these criteria, virtually all H influenzae isolates were susceptible to amoxicillin/clavulanate (98.3%), but only 5% were susceptible to cefaclor, azithromycin, or clarithromycin. 25 Thus, azithromycin may not be particularly effective for the treatment of AOM due to poor coverage of H influenzae at standard doses. ASiM: Do future trials need to consider the PCV-7 status of the children enrolled? Dr Block: I believe it is imperative that all future clinical trials of AOM address the PCV-7 status of the children enrolled in studies. As I alluded to earlier, the fourth or booster dose is probably much more important for protection against mucosal disease. Most penicillin-resistant pneumococcal strains are vaccine or vaccine-related serotypes. Our data suggest that the PCV-7 status of the study population may have a significant impact on the microbiologic and efficacy data obtained during the trial. Furthermore, it may not be valid to compare data from US children or those who have received PCV-7 with data from non-us children who have not received PCV-7. Except for Israel, non-us children usually have lower rates of infection due to H influenzae, particularly beta-lactamase positive strains. ASiM: Do you believe that future AOM treatment guidelines should consider the PCV-7 status of children, especially those aged 6 to 24 months? Dr Block: Definitely. At present amoxicillin/clavulanate is the only oral drug being recommended by the recent AAP/AAFP guidelines for AOM that fails to respond to initial antibiotic therapy. In the gram-negative era of PCV-7, thirdgeneration cephalosporins cefdinir and cefpodoxime, both of which have good coverage of H influenzae and most pneumococcus, should be included as routine second- or third-line choices along with amoxicillin/clavulanate. But in all fairness, when the current AAP/AAFP guidelines were developed, there were almost no data available on this microbial shift. Finally, because of its superior palatability and recent clinical trial data in PCV- 7 vaccinated children, cefdinir has an advantage over cefpodoxime liquid suspension. REFERENCES 1. Klein JO. Otitis media. Clin Infect Dis. 1994;19(5): Block SL, Hedrick J, Harrison CJ, et al. Community-wide vaccination with heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media. Pediatr Infect Dis J. 2004;23(9): Black S, Shinefeld H, Pireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J. 2000;19(3): Fireman B, Black SB, Shinefeld HR, Lee J, Lewis E, Ray P. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J. 2003;22(1): Erratum in: Pediatr Infect Dis J. 2003;22(2): Black S, Shinefeld H, Baxter R, et al. Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente. Pediatr Infect Dis J. 2004;23(6): Block SL, Hedrick JA, Harrison CJ. Widespread use of conjugated pneumococcal vaccine significantly reduces rates of AOM and antibiotic usage. Presented at: the Society for Pediatric Research; May 2004; San Francisco, Calif. Abstract Block SL, Harrison CJ, Hedrick J, Tyler R, Smith A, Hedrick R. Restricted use of antibiotic prophylaxis for recurrent acute otitis media in the era of penicillin non-susceptible Streptococcus pneumoniae. Int J Pediatr Otorhinolaryngol. 2001;61(1): Casey JR, Pichichero ME. Changes in frequency and pathogens causing acute otitis media in Pediatr Infect Dis J. 2004;23(9): American Academy of Pediatrics/American Academy of Family Physicians Subcommittee on Management of Acute Otitis Media. Clinical practice guideline: Diagnosis and management of acute otitis media. Pediatrics. 2004;113(5): Physicians Desk Reference. 58th ed. Montvale, NJ: Thomson PDR; Sader HS, Fritsche TR, Mutnick AH, Jones RN. Contemporary evaluation of the in vitro activity and spectrum of cefdinir compared with other orally administered antimicrobials tested against common respiratory tract pathogens ( ). Diagn Microbiol Infect Dis. 2003;47(3): Pichichero ME. Acute otitis media: part II. Treatment in an era of increasing antibiotic resistance. Am Fam Physician. 2000;61(8): Dandekar PK, Nicolau DP. Pharmacodynamic considerations for the selection of oral cephalosporins in the treatment of rhinosinusitis. Otolaryngol Head Neck Surg. 2002;127(6, suppl):s10-s Steele RW, Thomas MP, Begue RE. Compliance issues related to the selection of antibiotic suspensions for children. Pediatr Infect Dis J. 2001;20(1): Block SL, Busman TA, Paris MM, Bukofzer S. Comparison of 5 day cefdinir treatment with 10-day low dose amoxicillin/clavulanate treatment for acute otitis media. Pediatr Infect Dis J. 2004;23(9): Block SL, Harrison CJ, Hedrick JA, et al. Penicillin-resistant Streptococcus pneumoniae in acute otitis media, risk factors, susceptibility patterns and antimicrobial management. Pediatr Infect Dis J. 1995;14(9): S942 Vol. 4 (10E) December 2004

7 17. Rodriguez WJ, Schwartz RH. Streptococcus pneumoniae causes otitis media with higher fever and more redness of tympanic membranes than Haemophilus influenzae or Moraxella catarrhalis. Pediatr Infect Dis. 1999;18(10): Del Beccaro MA, Mendelman PM, Inglis AF, et al. Bacteriology of acute otitis media: a new perspective. J Pediatr. 1992;120(1): Piglansky L, Leibovitz E, Raiz S, et al. Bacteriologic and clinical efficacy of high dose amoxicillin for therapy of acute otitis media in children. Pediatr Infect Dis J. 2003;22(5): Block SL, Kratzer J, Nemeth MA, Tack KJ. Five-day cefdinir course vs. ten-day cefprozil course for treatment of acute otitis media. Pediatr Infect Dis J. 2000;19(suppl 12):S147-S Hoberman A, Paradise JL, Burch DJ, et al. Equivalent efficacy and reduced occurrence of diarrhea from a new formulation of amoxicillin/clavulanate potassium (Augmentin) for treatment of acute otitis media in children. Pediatr Infect Dis J. 1997;16(5): Carlin SA, Marchant CD, Shurin PA, Johnson CE, Super DM, Rehmus JM. Host factors and early therapeutic response in acute otitis media. J Pediatr. 1991;118(2): Jacobs MR. Optimisation of antimicrobial therapy using pharmacokinetic and pharmacodynamic parameters. Clin Microbiol Infect. 2001;7(11): Dagan R, Johnson CE, McLinn S, et al. Bacteriologic and clinical efficacy of amoxicillin/clavulanate vs. azitromycin in acute otitis media. Pediatr Infect Dis J. 2000;19(2): Jacobs MR. Building in efficacy: developing solutions to combat drug-resistant S pneumoniae. Clin Microbiol Infect. 2004;10(suppl 2): Advanced Studies in Medicine S943