Janet R. Casey

New patterns in the otopathogens causing acute otitis media six to eight years after introduction of pneumococcal conjugate vaccine.

Objective: To describe NP and AOM otopathogens during the time frame 2007 to 2009, 6 to 8 years after the introduction of 7-valent pneumococcal conjugate (PCV7) in the United States and to compare nasopharyngeal (NP) colonization and acute otitis media (AOM) microbiology in children 6 to 36 months of age having first and second AOM episodes with children who are otitis prone. Methods: Prospectively, the microbiology of NP colonization and AOM episodes was determined in 120 children with absent or infrequent AOM episodes. NP samples were collected at 7 routine visits between 6 and 30 months of age and at the time of AOM. For first and subsequent AOM episodes, middle ear fluid (MEF) was obtained by tympanocentesis. Eighty otitis prone children were comparatively studied. All 200 children received age-appropriate doses of PCV7. Results: We found PCV7 serotypes were virtually absent: (0.9% isolated from both NP and MEF) in both study groups. However, non-PCV7 serotypes replaced PCV serotypes such that the frequency of isolation of S. pneumoniae (Spn) was nearly equal to that of non-typeable Haemophilus influenzae (NTHi). M. catarrhalis (Mcat) was less common and Staphylococcus aureus infrequent in the NP and MEF from the 2 groups. The proportion of Spn, NTHi and Mcat causing AOM was similar in children with first and second AOM episodes compared to otitis prone children. However, oxacillin-resistant Spn isolated from the NP and MEF was 19% for the absent/infrequent and 58% for the otitis prone groups, P < 0.0001. Beta-lactamase producing NTHi occurred more frequently in the otitis prone group, P = 0.04. Conclusions: Six to 8 years after widespread use of PCV7, Spn strains expressing vaccine-type serotypes have virtually disappeared from the NP and MEF of vaccinated children. NP colonization and AOM has changed to non-PCV7 strains of Spn. NTHi continues to be a major AOM pathogen. The otopathogens in first and second AOM and in otitis prone children are very similar although Spn and NTHi are more often antibiotic resistant in the otitis prone.

Comparative trial of the safety and immunogenicity of quadrivalent (A, C, Y, W-135) meningococcal polysaccharide-diphtheria conjugate vaccine versus quadrivalent polysaccharide vaccine in two- to ten-year-old children.

Background: A quadrivalent meningococcal diphtheria conjugate vaccine (MCV-4) has been developed to provide T-cell dependent immune responses against 4 major disease-causing serogroups (A, C, Y, W-135). Methods: In a comparative, randomized, modified double blind, controlled study in healthy 2- to 10-year-old U.S. children, safety and immunogenicity profiles of MCV-4 (n = 696) were compared with those of a licensed quadrivalent polysaccharide vaccine, Menomune A/C/Y/W-135 (PSV-4, n = 702). Vaccine-related adverse reactions were assessed for 28-day and 6-month follow-up periods. Serum bactericidal activity (SBA) was assayed in prevaccination, day 28 and 6-month postvaccination sera samples. Results: Both vaccines were well-tolerated, with no vaccine-related serious adverse events and similar rates of mostly mild local and systemic reactions. Functional antibody (SBA) seroconversion percentages were significantly higher for all 4 serogroups in the MCV-4 group. The SBA geometric mean titers against serogroups A, C, Y and W-135 with MCV-4 were 1700, 354, 637 and 750, respectively, compared with PSV-4 (893, 231, 408 and 426) 28 days postvaccination (P < 0.001 for all comparisons). This significant difference persisted through 6 months. Conclusions: In 2- to 10-year-old children MCV-4 had a safety profile similar to that of PSV-4 and elicited significantly higher and more persistent serum bactericidal antibody responses against meningococcal serogroups A, C, Y and W-135 than did the licensed polysaccharide vaccine.

Safe use of selected cephalosporins in penicillin-allergic patients: A meta-analysis

Background Recent analysis of clinical data and a clearer understanding of the role of chemical structure in the development of cross-reactivity indicate that the increased risk of an allergic reaction to a cephalosporin in penicillin-allergic patients is smaller than previously postulated. Method Medline and EMBASE databases were searched with the keywords: cephalosporin, penicillin, allergy, and crosssensitivity for the years 1960 through 2005. Among 219 articles retrieved, 9 served as source material for this evidence-based meta-analysis. Results A significant increase in allergic reactions to cephalothin (odds ratio [OR] = 2.5; 95% confidence interval [CI] = 1.1 to 5.5), cephaloridine (OR = 8.7; CI = 5.9 to 12.8), and cephalexin (OR = 5.8; CI = 3.6 to 9.2), and all first generation cephalosporins plus cefamandole (OR = 4.8; CI = 3.7 to 6.2) were observed in penicillin allergic patients; no increase was observed with second generation cephalosporins (OR = 1.1; CI, 0.6 to 2.1) or third generation cephalosporins (OR = 0.5; CI = 0.2 to 1.1). Clinical challenges, skin testing, and monoclonal antibody studies point to the paramount importance of similarities in side chain structure to predict cross-allergy between cephalosporins and penicillins. Conclusion First-generation cephalosporins have cross-allergy with penicillins, but cross-allergy is negligible with second-and third-generation cephalosporins. Particular emphasis should be placed on the role of chemical structure in determining the risk of cross-reactivity between specific agents. 2007 American Academy of Otolaryngology-Head and Neck Surgery Foundation. All rights reserved.

Acute Otitis Media Otopathogens during 2008-2010 in Rochester NY

Background: The otopathogen distribution colonizing the nasopharynx (NP) and causing acute otitis media (AOM) is in flux following the introduction of pneumococcal conjugate vaccine 7 (PCV7) and will continue to change. Methods: Two hundred seventy-seven children were followed prospectively; tympanocentesis was performed during AOM and 208 NP samples were collected to compare with middle ear fluid (MEF) isolates. Eight hundred sixty-three NP samples were collected at 7 healthy visits between 6 and 30 months of age. All children received PCV7 until April 2010 when it was substituted by PCV13. Multilocus sequence typing was used to speciate Streptococcus pneumoniae. Results: The distribution of otopathogens in the MEF during the study time frame was stable. PCV7 serotypes of pneumococci were virtually absent. The frequency of isolation of S. pneumoniae was 26–36% compared with 28–34% for nontypeable Haemophilus influenzae. Moraxella catarrhalis isolation was less common, 7–18%. The proportion of S. pneumoniae that were penicillin nonsusceptible was stable during the 3 years, 40–52%. All M. catarrhalis and 34% of nontypeable H. influenzae were &bgr;-lactamase producing. NP isolates of otopathogens at onset of AOM included the isolate from the MEF and was dissimilar from the distribution at times of health. Sequence types 320 and 199 of S. pneumoniae expressing serotypes 19A and 15 most often caused AOM. Conclusions: The otopathogen distribution, antibiotic susceptibility and the diversity of strains within the S. pneumoniae species during 2008 through late 2010 were stable. NP isolation of otopathogens at onset of AOM better reflected, albeit incompletely, likely MEF isolates compared with NP isolates at times of health.

Penicillin failure in streptococcal tonsillopharyngitis: causes and remedies.

Synopsis. Penicillin administered for 10 days has been the treatment of choice for group A beta-hemolytic streptococcal tonsillopharyngitis since the 1950s. The bacteriologic failure rate of 10 days of penicillin therapy ranged from approximately 2 to 10% until the early 1970s. Beginning in the late 1970s bacteriologic and clinical failure rates with penicillin therapy began to increase steadily over time and are now reported to be approximately 30%. The primary cause of penicillin treatment failure in streptococcal tonsillopharyngitis may be lack of compliance with the 10-day therapeutic regimen. Other causes of penicillin treatment failure include reexposure to Streptococcus-infected family members or peers; copathogenicity, in which bacteria susceptible to a class of drugs are protected by other, colocalized bacterial strains that lack the same susceptibility; antibiotic-associated eradication of normal protective pharyngeal flora; and penicillin tolerance, whereby streptococcal bacteria repeatedly or continuously exposed to sublethal concentrations of antibiotic become increasingly resistant to eradication. Although 10 days of penicillin therapy is effective in the management of tonsillopharyngitis for many patients, multiple factors may, singly or together, cause treatment failure. A number of antibiotics, particularly the cephalosporins, have been demonstrated to be superior to penicillin at eradicating group A beta-hemolytic Streptococcus, and several are effective when administered for 4 to 5 days. Conclusions. Ten days of penicillin therapy may not be the best therapeutic choice for all pediatric patients. Other antibiotics, shortened courses of the cephalosporins in particular, may be preferable in some cases.

Breast-feeding is associated with a reduced frequency of acute otitis media and high serum antibody levels against NTHi and outer membrane protein vaccine antigen candidate P6.

Nontypeable Haemophilus influenzae (NTHi) causes acute otitis media (AOM) in infants. Breast-feeding protects against AOM and/or nasopharyngeal (NP) colonization; however, the mechanism of protection is incompletely understood. Children with AOM and healthy children were studied according to feeding status: breast-fed, breast/formula fed, or formula fed. Cumulative episodes of AOM, ELISA titers of serum IgG antibodies to whole-cell NTHi and vaccine candidate outer membrane protein P6, bactericidal titers of serum and NP colonization by NTHi were assessed. A lower incidence of AOM was found in breast- versus formula-fed children. Levels of specific serum IgG antibody to NTHi and P6 were highest in breast-fed, intermediate in breast/formula fed, and lowest in formula-fed infants. Serum IgG antibody to P6 correlated with bactericidal activity against NTHi. Among children with AOM, the prevalence of NTHi in the NP was lower in breast- versus nonbreast-fed infants. We conclude that breast-feeding shows an association with higher levels of antibodies to NTHi and P6, suggesting that breast-feeding modulates the serum immune response to NTHi and P6. Higher serum IgG might facilitate protection against AOM and NP colonization in breast-fed children.

Pathogens Causing Recurrent and Difficult-to-Treat Acute Otitis Media, 2003-2006

This study sought to determine the microbiology of recurrent acute otitis media (AOM) and AOM treatment failure (AOMTF) in the context of widespread use of heptavalent pneumococcal conjugate vaccine (PCV7). In this retrospective cohort study, 244 AOM isolates obtained by tympanocentesis during 3 respiratory seasons—2003-2004 (n = 126), 2004-2005 (n = 52), 2005-2006 (n = 66)—from three geographically diverse pediatric populations were compared. Most isolates were from children less than 2 years old, who had received PCV7. For the 3 seasons the proportion of Streptococcus pneumoniae isolates was 35%, 35%, and 46% and for Haemophilus influenzae was 55%, 58%, and 39%, respectively (change in trend, P = .09). A total of 37%, 39%, and 50% of S. pneumoniae were penicillin nonsusceptible (PNSP) and 48%, 67%, and 50% of H. influenzae produced β-lactamase, respectively. Although H. influenzae remains the most frequently isolated pathogen in children with AOMTF or recurrent AOM, S. pneumoniae that are PNSP are reemerging as important organisms.

Systematic review of factors contributing to penicillin treatment failure in Streptococcus pyogenes pharyngitis

Objective Review the evidence for various explanations for microbiologic treatment failure following use of penicillin in group A streptococcal (GAS) tonsillopharyngitis. DATA SOURCE Systematic review of the literature based on Medline and EMBASE searches, and review of reference lists of included studies. RESULTS The explanations for penicillin treatment failure in GAS tonsillopharyngitis include 1) carrier state, 2) lack of compliance, 3) recurrent exposure, 4) in vivo copathogenicity of β-lactamase–producing normal pharyngeal flora, 5) in vivo bacterial coaggregation, 6) poor antibiotic penetration to tonsillopharyngeal tissue, 7) in vivo eradication of normal protective flora, 8) early initiation of antibiotic therapy resulting in suppression of an adequate host immune response, 9) intracellular localization of GAS, 10) GAS tolerance to penicillin, 11) contaminated toothbrushes or orthodontic appliances, and 12) transmission from the family pet. There is very little type I or II evidence to support any of the above-cited explanations for treatment failure in GAS tonsillopharyngitis; available studies are mostly observational (in patients) or laboratory-based without clinical confirmation. CONCLUSION Multiple explanations have been offered by investigators to explain penicillin treatment failures in GAS tonsillopharyngitis, but the evidence base to support the proposed explanations is generally weak by current standards. Further research is needed to better understand the mechanism(s) of penicillin treatment failure in GAS tonsillopharyngitis.

Meta-analysis of Cephalosporins versus Penicillin for Treatment of Group A Streptococcal Tonsillopharyngitis in Adults

We conducted a meta-analysis of 9 randomized controlled trials (involving 2113 patients) comparing cephalosporins with penicillin for treatment of group A beta -hemolytic streptococcal (GABHS) tonsillopharyngitis in adults. The summary odds ratio (OR) for bacteriologic cure rate significantly favored cephalosporins, compared with penicillin (OR,1.83; 95% confidence interval [CI], 1.37-2.44); the bacteriologic failure rate was nearly 2 times higher for penicillin therapy than it was for cephalosporin therapy (P=.00004). The summary OR for clinical cure rate was 2.29 (95% CI, 1.61-3.28), significantly favoring cephalosporins (P<.00001). Sensitivity analyses for bacterial cure significantly favored cephalosporins over penicillin in trials that were double-blinded and of high quality, trials that had a well-defined clinical status, trials that performed GABHS serotyping, trials that eliminated carriers from analysis, and trials that had a test-of-cure culture performed 3-14 days after treatment. This meta-analysis indicates that the likelihood of bacteriologic and clinical failure in the treatment of GABHS tonsillopharyngitis is 2 times higher for oral penicillin than for oral cephalosporins.

Serum Antibody Response to Five Streptococcus pneumoniae Proteins during Acute Otitis Media in Otitis Prone and Non-Otitis Prone Children

Background: Streptococcus pneumoniae (Spn) is one of the common bacteria responsible for episodic acute otitis media (AOM; non–otitis-prone), recurrent AOM (otitis-prone), and AOM treatment failure (AOMTF) in children. Objective: From a population of 268 children, we sought to compare the serum IgG antibody titers of 5 different Spn proteins (PhtD, LytB, PcpA, PhtE, and Ply) that are vaccine candidates in children with episodic AOM (n = 34), who were otitis prone (n = 35) and who had AOMTF (n = 25) caused by Spn. Methods: Antibody was quantitated by enzyme-linked immunosorbent assay. Results: At their AOM visit, anti-PhtD, -LytB, -PhtE, and -Ply IgG antibody titers in otitis-prone children were significantly lower compared with non–otitis-prone children (P < 0.05) and children with AOMTF (P < 0.05). On comparing acute to convalescent geometric mean IgG antibody titers after AOM against the 5 proteins we found that otitis-prone, AOMTF, and non-otitis-prone children had no significant change in titers (except for PhtE in children with AOMTF), but detailed analysis showed that about one-third of the children in each cohort had a 2-fold rise in antibody to the studied antigens. Although non–otitis-prone children had significant increases (P < 0.001) between 6 and 24 months of age in anti-PhtD, PcpA, PhtE, and Ply IgG antibody titers as a consequence of nasopharyngeal colonization and AOM, otitis-prone children either failed to show rises or the rises were significantly less than the non–otitis-prone children. Conclusion: Otitis-prone and AOMTF children mount less of an IgG serum antibody response as compared with non–otitis-prone children to Spn proteins after AOM and nasopharyngeal colonization.