Published online June 1, 2006
PEDIATRICS Vol. 117 No. 6 June 2006, pp. e1087-e1094 (doi:10.1542/peds.2005-2651)
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Empiric First-line Antibiotic Treatment of Acute Otitis in the Era of the Heptavalent Pneumococcal Conjugate Vaccine

Jane Garbutt, MB, ChBa,b, Isabel Rosenbloom, MDb, Jenny Wua and Gregory A. Storch, MDb

a Division of General Medical Sciences
b Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. Our goal was to estimate the local prevalence of Streptococcus pneumoniae nonsusceptible to penicillin and amoxicillin after widespread use of the heptavalent pneumococcal vaccine and to revise community-specific recommendations for first-line antibiotic treatment of acute otitis media.

METHODS. We conducted serial prevalence surveys between 2000 and 2004 in the offices of community pediatricians in St Louis, Missouri. Study participants were children <7 years of age with acute upper respiratory infections. Children treated with an antibiotic in the past 4 weeks were excluded. S pneumoniae was isolated from nasopharyngeal swabs using standard techniques. Isolates with a penicillin minimum inhibitory concentration >2 µg/mL were considered to be S pneumoniae nonsusceptible to amoxicillin.

RESULTS. There were 327 patients enrolled in the study. Between 2000 and 2004, vaccine coverage with ≥3 doses of heptavalent pneumococcal vaccine increased from 0% to 54%, but nasopharyngeal carriage of S pneumoniae was stable at 39%. The prevalence of S pneumoniae nonsusceptible to penicillin fell from 25% to 12% among patients, did not vary if <2 years of age, was reduced in children with ≥3 doses of heptavalent pneumococcal vaccine, and increased in child care attendees but reduced in attendees who had ≥3 doses of heptavalent pneumococcal vaccine. The prevalence of S pneumoniae nonsusceptible to amoxicillin in patients remained <5%.

CONCLUSIONS. In our community, widespread use of heptavalent pneumococcal vaccine has reduced the prevalence of S pneumoniae nonsusceptible to penicillin, and the prevalence of S pneumoniae nonsusceptible to amoxicillin remains low (<5%). If antibiotic treatment is elected for children with uncomplicated acute otitis media, we recommend treatment with standard-dose amoxicillin (40–45 mg/kg per day) for children with ≥3 doses of heptavalent pneumococcal vaccine, regardless of age and child care status. High-dose amoxicillin should be used for children with <3 doses of heptavalent pneumococcal vaccine and those treated recently with an antibiotic.

Key Words: Streptococcus pneumoniae • acute otitis media • conjugated pneumococcal vaccine • treatment guidelines

Abbreviations: AOM—acute otitis media • MIC—minimum inhibitory concentration • NSSP—Streptococcus pneumoniae nonsusceptible to penicillin • NSSP-A—Streptococcus pneumoniae nonsusceptible to amoxicillin • PCV7—heptavalent pneumococcal conjugate vaccine • CI—confidence interval • OR—odds ratio

Although antibiotic prescribing has declined in the past 10 years, acute otitis media (AOM) remains the most common condition for which children in the United States are treated with an antibiotic.1,2 The most recent national clinical practice guidelines for the treatment of children with uncomplicated AOM suggest 2 different approaches depending on the child's age and illness severity and the physician's diagnostic certainty.3 If there is a ready means for the parent to communicate with the physician, it is recommended that the physician consider using symptomatic treatment with careful observation of the child for 48 to 72 hours for all children with nonsevere disease (mild otalgia and fever <39°C) who are ≥2 years of age. For children who are 6 months to 2 years of age, this "observation option" should only be considered for children with nonsevere disease in whom the diagnosis is uncertain. For all children with severe disease (moderate-to-severe otalgia or fever ≥39°C) and younger children with a certain diagnosis of AOM, treatment with high-dose amoxicillin (80–90 mg/kg per day) is recommended.

Amoxicillin is selected to treat Streptococcus pneumoniae, the bacterial pathogen most frequently associated with AOM and the least likely to resolve spontaneously.4,5 To provide effective treatment of S pneumoniae, the prescribed dose of amoxicillin must be adequate to maintain the serum concentration above the minimum inhibitory concentration (MIC) for 40% to 50% of the dosing interval.6,7 Over the past 20 years, the recommended MIC cut point for susceptibility of S. pneumoniae to ß-lactam antibiotics has been raised in concert with the rising prevalence of nonsusceptible isolates.4,8–10 Since 2000, the MIC cut points for susceptibility to penicillin and amoxicillin have differed such that isolates of S pneumoniae with penicillin MIC ≤2 µg/mL are considered to be susceptible to amoxicillin but may be nonsusceptible to penicillin (MIC ≥0.12 µg/mL).11 Although current recommendations for empiric antibiotic treatment of AOM focus on amoxicillin, amoxicillin susceptibility is not routinely tested or reported. High-dose amoxicillin may not be needed if the local prevalence of S pneumoniae nonsusceptible to penicillin (NSSP) and amoxicillin (NSSP-A) is low.4 In addition, widespread use of the heptavalent pneumococcal conjugate vaccine (PCV7) since the year 2000 may obviate the need for high-dose amoxicillin treatment for AOM.

The conjugated vaccine contains polysaccharides of the 7 S pneumoniae serotypes most commonly associated with invasive pneumococcal disease in children in the United States. Five of these serotypes account for most of the antibiotic resistance among pneumococci, including high-level resistance to penicillin, macrolide resistance, and multidrug resistance.12 Postlicensure studies have reported a significant reduction in pneumococcal invasive diseases because of vaccine and vaccine-related serotypes,13 a decline in the prevalence of serotypes with resistance to penicillin,14–17 a reduction in the total number of AOM episodes in children <2 years old by 6% to 9%,18–21 and a reduction in AOM treatment failures.17 The impact of widespread use of PCV7 on the epidemiology of AOM in the community is not known but may require reevaluation of AOM treatment guidelines.

The objectives of this study were twofold: (1) to estimate the local prevalence of nonsusceptible S pneumoniae (NSSP and NSSP-A) in children with acute upper respiratory illnesses in our community after the widespread use of PCV7, and (2) to review and, if necessary, revise our local recommendations for the first-line empiric treatment of AOM.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Population
Over the 5-year study period, specimens were collected from pediatric offices in St Louis from March 14 to May 11, 2000 (6 offices); from February 12 to April 4, 2001 (5 offices); from March 1 to April 9, 2003 (5 offices); and from February 23 to April 5, 2004 (4 offices). No patients were enrolled in 2002 because of a funding deficit. Offices were selected to provide a demographic cross-section of patients and were located throughout the metropolitan area. Only 1 practice participated in every year of data collection. Most participating pediatricians were members of the Washington University Pediatric and Adolescent Ambulatory Research Consortium, a practice-based research network of community pediatricians. The study was approved by the Washington University Human Studies Committee, and all of the parents provided informed consent.

Study methods have been described in detail previously.22 Briefly, study subjects were children <7 years of age with a new diagnosis of AOM, otitis media with effusion, acute sinusitis, streptococcal pharyngitis, nonspecific upper respiratory infection, or cough illness. Standardized diagnostic criteria were used throughout the study (Table 1). Patients were invited to participate during the office visit, but if the office was very busy, not all of the patients were approached. Patients were excluded if they had received an antibiotic in the past month, had a serious concurrent illness, or were treated with immunosuppressive drugs (including systemic steroids). Each child was enrolled once only, and siblings of patients already enrolled in the study were excluded.


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  		TABLE 1 Diagnostic Criteria Used to Identify Study Patients

 
Measurement
A posterior nasopharyngeal swab was obtained from each child. The swab was plated onto sheep blood agar in the office and transported to the microbiology laboratory within 12 hours. It was incubated for 24 to 48 hours at 35°C in 5% CO2-enriched atmosphere. S pneumoniae was identified based on {alpha} hemolysis and susceptibility to Optochin. Antibiotic susceptibilities were determined using the Kirby-Bauer method and E-strips.11,23 Susceptibility to penicillin and amoxicillin was defined using National Committee for Clinical Laboratory Standards.11 For the first 2 years of the study, susceptibility to amoxicillin was not tested directly but was defined in terms of penicillin resistance. Isolates with a penicillin MIC >2 µg/mL were considered to be resistant to standard-dose amoxicillin (NSSP-A). In 2003 and 2004, amoxicillin susceptibility was measured directly using the Pasco Panel (BD Diagnostics, Sparks, MD). Throughout the study period, isolates were also tested for susceptibility to other ß-lactam antibiotics (cefotaxime, cefriaxone, and cefepime were added in 2003/2004), macrolides (erythromycin), trimethoprim-sulfamethoxazole, vancomycin, clindamycin (not tested in 2003), and quinolones (ofloxacin and levofloxacin added in 2003/2004). In 2003 and 2004, isolates were also tested for susceptibility to tetracycline. For each of these antibiotics, isolates were classified as susceptible or resistant (high level or intermediate level).

The parent completed a brief questionnaire that inquired about known risk factors for infection with NSSP and demographic information. The physician completed a 1-page questionnaire that detailed comorbidities, use of PCV7, duration of symptoms, and the diagnosis and antibiotic treatment given. Unanticipated initial demand and problems with vaccine production resulted in reduced availability of vaccine and variation in the recommended vaccine schedule at times during the study period.24 However, because 3 doses of vaccine were recommended for all of the children initiating vaccination with PCV7 <12 months of age unless vaccine shortage was severe, we defined vaccination with PCV7 as receipt of ≥3 doses.

Statistical Analysis
The primary end points were the prevalence of S pneumoniae, NSSP, and NSSP-A in patients in the study population. To identify factors that significantly affected the risk of carriage of S pneumoniae, NSSP, and NSSP-A, we used the {chi}2 test or Fisher's exact test to compare proportions within the pooled study populations and logistic regression in bivariate analyses to calculate odds ratios, controlling for time. To examine change over time, we used Cuzick's test for trend.25 Finally, we used logistic regression to examine whether child care attendance, young age (<2 years vs ≥2 years) and vaccination with PCV7 (≥3 doses versus fewer or no doses) were independently associated with carriage of S pneumoniae, NSSP, and NSSP-A, controlling for time, race (white versus other), health insurance (Medicaid versus other), and having ≥1 other child at home. Statistical significance was defined as P < .05 (2-tailed for all tests). All of the statistical analyses were performed by using Stata 7.0 (Stata Corp, College Station, TX).


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Patients
The 327 study participants were drawn from all regions of the St Louis metropolitan area; 169 (52%) were <2 years of age, and 117 (36%) attended child care (Table 2). The most frequent diagnoses were nonspecific upper respiratory infection (34%) and AOM (29%). In 2003, we were unable to enroll patients from the city of St Louis, altering the demographic profile of study participants for that year (Table 2). Pneumococcal vaccine was not used in 2000. In 2001, 2003, and 2004, 47%, 79%, and 86%, respectively, of patients had received ≥1 dose of the conjugate vaccine, and 18%, 59%, and 54%, respectively, had received ≥3 doses (Table 2). Data from 2000 and 2001 have been presented previously22 but are included here to permit comparison before and after the widespread use of PCV7. Data from nonparticipants are not available.


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  		TABLE 2 Characteristics of 327 Study Participants

 
Nasopharyngeal Carriage of S pneumoniae
Overall, nasopharyngeal carriage of S. pneumoniae was 39% (95% confidence interval [CI]: 34%–45%), and did not differ by study year (P = .53; Table 3). Carriage was increased in child care attendees compared with nonattendees (52% vs 33%; P = .001; odds ratio [OR]: 2.2; 95% CI: 1.4 to 3.5). Carriage was not increased in young children (44% <2 years, 34% ≥2 years; P = .08; OR: 1.5; 95% CI: 0.8 to 1.2) and did not vary by vaccine status for PCV7 (37% vs 41%; P = .5). In the multivariate analyses, child care attendance (OR: 2.4; 95% CI: 1.5 to 4.0) and young age (OR: 1.6; 95% CI: 1.0 to 2.7) were independent predictors of carriage of S pneumoniae, and vaccination with PCV7 (≥3 doses of PCV7 or fewer) was not protective (OR: 0.6; 95% CI: 0.3 to 1.2).


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  		TABLE 3 Nasopharyngeal Carriage of S pneumoniae and Nonsusceptible S pneumoniae in 327 Children With Acute Upper Respiratory Illnesses

 
Nasopharyngeal Carriage of NSSP
The prevalence of NSSP decreased during the 5-year study period (Table 3). Between 2000 and 2004, the prevalence of NSSP among isolates of S pneumoniae fell from 59% to 34% (P = .02), and the prevalence among patients fell from 25% to 12% (P = .02). The largest decrease in isolates with both high-level and intermediate resistance to penicillin occurred between 2000 and 2001 (Table 3). Subsequently, the prevalence of isolates with high-level resistance continued to decline, whereas the prevalence of isolates with intermediate resistance slowly increased to almost pre-PCV7 levels.

Carriage of NSSP was increased in child care attendees compared with nonattendees (25% vs 13%; P = .005; OR: 2.1; 95% CI: 1.2 to 3.9) but not in young children (19% <2 years, 14% ≥2 years; P = .2; OR: 1.3; 95% CI: 0.7 to 2.4). Carriage of NSSP was decreased in children who had received ≥3 doses of PCV7 compared with those who had received fewer or no doses (8% vs 20%; P = .009; OR: 0.4; 95% CI: 0.15 to 1.07) but did not differ among children who had received ≥1 dose of PCV7 compared with unvaccinated children (13% vs 20%; P = .08).

In the multivariate analysis, child care attendance was an independent predictor of carriage of NSSP (OR: 2.3; 95% CI: 1.2 to 4.4; P = .009), and vaccination with ≥3 doses of PCV7 was protective (OR: 0.3; 95% CI: 0.1 to 0.9; P = .034). Vaccine status measured as ≥1 dose of PCV7 was not protective (OR: 0.8; 95% CI: 0.3 to 2.1; P = .6).

The results of a subgroup analysis of 319 children for whom the status for PCV7 vaccination and child care attendance were known are presented in Table 4. Among child care attendees, the prevalence of NSSP in children with ≥3 doses of PCV7 was 7% (2 of 29, both isolates had intermediate resistance to penicillin) and was 31% (28 of 89) in children who had received <3 doses of PCV7 (15% high-level, 17% intermediate).


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  		TABLE 4 Prevalence (95% CI) of NSSP and NSSP-A by Attendance at Child Care and Vaccination Status with PCV7

 
Nasopharyngeal Carriage of NSSP-A
The prevalence of NSSP-A was low throughout the study period and did not vary by study year (Table 3). The overall prevalence of NSSP-A was 6% (95% CI: 2% to 10%) among S pneumoniae isolates and 2% (95% CI: 0.8% to 4.0%) in the 327 study patients. Carriage of NSSP-A was increased in child care attendees compared with nonattendees (5% vs 1%; P = .028; OR: 5.3; 95% CI: 1.0 to 26.8) but not in young children (3% vs 2%; P = .5). Although NSSP-A was not isolated from any child who had received ≥3 doses of PCV7, NSSP-A carriage did not differ significantly with vaccine status (0 if ≥3 doses vs 3% if <3 doses; P = .21; 1% if ≥1 dose vs 3% if unvaccinated; P = .47). In the multivariate analysis, child care attendance increased the risk of nasopharyngeal carriage of NSSP-A (OR: 7.5; 95% CI: 1.3 to 44.3) when vaccine status was measured as ≥1 dose of PCV7. Because receipt of ≥3 doses of vaccine perfectly predicted the absence of NSSP-A, we were unable to use this variable in the multivariate analysis.

Multidrug-Resistant S pneumoniae
Among NSSP isolates, 53 (96%) of 55 were resistant to ≥1 other antibiotic, and many isolates were resistant to several non-ß-lactam classes of antibiotics: 14 (25%) were resistant to 1 other antibiotic class, 24 (44%) to 2 classes, 7 (13%) to 3 classes, and 1 (2%) isolate was resistant to 4 additional classes. All of the isolates with high-level resistance to penicillin were resistant to trimethoprim-sulfamethoxazole and to all of the ß-lactam antibiotics tested.

None of the 8 NSSP-A isolates were resistant to clindamycin or vancomycin, but all were resistant to other ß-lactam antibiotics. One isolate was resistant to 1 additional drug class, 6 were resistant to 2 classes, and 1 was resistant to 3 additional classes.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Our findings have important implications for first-line empiric antibiotic treatment of AOM in our community. The probability that infection was because of S pneumoniae that was resistant to penicillin decreased significantly between 2000 and 2004, and the probability that infection was because of S pneumoniae resistant to amoxicillin remained low (<5%). The most likely explanation for the significant reduction in resistant isolates in our community and in other areas of the United States16,21 is the direct and indirect effects of the introduction and widespread use of PCV7. Reduction in antibiotic prescribing for children occurring nationally1,2 may have also contributed.26 Others have observed an increase in AOM cases because of Haemophilus influenzae in the post-PCV7 era, particularly in refractory or recently treated cases.16,17 However, the stable rate of carriage of S pneumoniae in symptomatic children in our community suggests that the probability that AOM is caused by this bacteria has not changed significantly. We were unable to identify S pneumoniae serotypes in this study, but it is likely that PCV7 serotypes resistant to ß-lactam antibiotics were replaced by susceptible nonvaccine serotypes.16,27

Although ≤5% of symptomatic children carried penicillin-resistant or amoxicillin-resistant S pneumoniae in their nasopharynx, the predictive value of this test for the presence of S pneumoniae in middle ear fluid is <50%,28,29 suggesting that <5% of local children with AOM symptoms will have resistant pneumococci in their middle ear. Pharmacodynamic and clinical studies suggest that standard-dose amoxicillin (40–45 mg/kg per day) will effectively treat all middle ear infections caused by isolates of S pneumoniae with a penicillin MIC ≤2 µg/mL (ie, all isolates other than NSSP-A).6,22,30–34 Consequently, standard-dose rather than high-dose (80–90 mg/kg per day) amoxicillin should provide effective treatment for most children in our community who have uncomplicated AOM and require antibiotic treatment. These treatment recommendations may need to be revised if the distribution of bacterial pathogens changes.

Recent national guidelines do not suggest tailoring AOM management to reflect a patient's child care attendance or their PCV7 status. However, our data suggest that these factors have an important effect on the probability of infection with nonsusceptible S pneumoniae. Child care attendees were more likely than nonattendees to have NSSP and NSSP-A in their nasopharynx, and children vaccinated with ≥3 doses of PCV7 were protected from colonization with resistant strains, regardless of their child care status. This means that for vaccinated children in whom antibiotic treatment is required, standard-dose amoxicillin should provide effective treatment, regardless of their child care status. Carriage of NSSP-A was highest in child care attendees who had not received ≥3 doses of PCV7, suggesting that this group of children is more likely to require antibiotic treatment with high-dose amoxicillin. Although vaccination with PCV7 is recommended for all children,35 vaccine coverage may be incomplete.36 Because child care attendance is a key factor in the transmission of S pneumoniae at both the individual and community level,37 administration of ≥3 doses of PCV7 must be a priority for all child care attendees. Young age (<2 years) has been associated with increased risk of NSSP infections4,38 but did not increase carriage of NSSP or NSSP-A in the study population. These findings suggest that if antibiotic treatment is elected, standard-dose amoxicillin may be used for children in our community who have been vaccinated with ≥3 doses of PCV7, regardless of their child care status and age. High-dose amoxicillin should be used for children who have received fewer doses of PCV7 or who have not been vaccinated.

The increasing prevalence of isolates with intermediate resistance to penicillin in the last 2 years is worrying. Although this finding may be artifactual and simply reflect unstable numbers in our small sample, it has been noted in other communities27and may reflect an adaptive response of nonvaccine serotypes of S pneumoniae to the widespread use of high-dose amoxicillin, amoxicillin-clavanulate, or other broad-spectrum antibiotics. Avoidance of unnecessary antibiotic use continues to be imperative in maintaining the antimicrobial susceptibility of these strains. To this end, we support the recent evidence-based national AOM practice guidelines that suggest the use of symptomatic treatment and careful observation as the first-line treatment of uncomplicated AOM in children who have nonsevere disease.3 These recommendations are further supported by a recent, carefully conducted, randomized, controlled trial comparing high-dose amoxicillin and watchful waiting for children with nonsevere AOM.39 This study found that, although immediate antibiotic treatment resulted in fewer treatment failures, 66% of children in the watchful waiting group did not require antibiotic treatment, and parental satisfaction with treatment was the same for both groups. Also, treatment failure, recurrence, and cure rates did not differ by age. These findings suggest that symptomatic treatment and careful observation can be considered as an initial treatment option for all children with nonsevere AOM, regardless of age and diagnostic certainty. A recent study suggests that many parents are willing to try this observation option for AOM.40 An implementation strategy that has been used successfully is the safety-net antibiotic prescription, when the provider prescribes an antibiotic but recommends a brief trial of symptomatic treatment before filling the prescription.41

There are several limitations to our study. Although study sites were selected to ensure that specimens were collected from geographically varied parts of the metropolitan area and demographically diverse patients, our sample was from 1 geographic area, and our findings may not generalize to other settings. In addition, samples were collected during the same time period each year, possibly limiting generalization to other seasons of the year. Our sample was small, limiting our power for subgroup analyses. Patients were not randomly selected, and we do not have data to characterize nonparticipants. However, all of the patients included in the analyses were independent, and we do not believe that nonparticipants differed systematically in their PCV7 and child care status. Also, we do not have data to make specific recommendations for antibiotic treatment depending on disease severity, and our conclusions may not apply to children who have been treated with an antibiotic in the past month. Finally, nasopharyngeal carriage of S pneumoniae does not confirm that the organism is pathogenic for AOM, but nasopharyngeal colonization patterns are reasonable surrogates for antibiotic resistance among AOM pathogens42 and provide useful data to inform local treatment recommendations.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Among children in the St Louis area with acute upper respiratory infections who have not received an antibiotic in the prior 4 weeks, the probability that infection is caused by S pneumoniae, which is not susceptible to standard-dose amoxicillin, is <5% and is lower in children who have been vaccinated with ≥3 doses of PCV7. We support the national recommendations that symptomatic treatment and careful observation be considered for the first-line management of most children with nonsevere, uncomplicated AOM. However, if antibiotic treatment is elected, then standard-dose amoxicillin may be used for most children in our community who have been vaccinated with ≥3 doses of PCV7, regardless of their child care status and age. High-dose amoxicillin should be used for children who have received fewer doses of PCV7 or who have not been vaccinated. Future studies should assess changes in the distribution of AOM bacterial pathogens in the post-PCV7 era.


   ACKNOWLEDGMENTS
 
This work was supported by a grant from the St Louis Children's Hospital Medical Staff.

We thank the following community pediatricians and their office staffs for their help with enrolling study patients and obtaining nasopharyngeal specimens (most participating pediatricians are members of Washington University Pediatric and Adolescent Ambulatory Research Consortium, a practice-based network of community pediatricians affiliated with Washington University in St Louis): Rubilinda Casino, MD, John Davies, MD, Jay Epstein, MD, Diane Eschmann-Moire, MD, Anna Fitz-James, MD, Elliot Gellman, MD, David Hartenbach, MD, Jack Land, MD, Ariane May, MD, Kevin Murphy, MD, Tasmin Najaf, MD, Alison Nash, MD, Homer Nash, MD, Karen Norton, MD, Peter Putnam, MD, Christina Ruby-Zeigler, MD, Daniel Rudolph, MD, Blaine Sayre, MD, Margaret Schmandt, MD, Gary Sherman, MD, Paul Simons, MD, Mary Tillman, MD, and Patricia Wolfe, MD. We also thank Janet Cromian, Rhonda Ferret, Pat Sellenriek, and the staff at St Louis Children's Hospital Laboratory for their help with the study.


   FOOTNOTES
 
Accepted Dec 14, 2005.

Address correspondence to Jane M. Garbutt, MB, ChB, Campus Box 8005, 660 South Euclid Ave, St Louis, MO 63110. E-mail: jgarbutt{at}im.wustl.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



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M. E. Pichichero and J. R. Casey
Emergence of a Multiresistant Serotype 19A Pneumococcal Strain Not Included in the 7-Valent Conjugate Vaccine as an Otopathogen in Children
JAMA, October 17, 2007; 298(15): 1772 - 1778.
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