[Efficacy and safety of clavulanic acid/amoxicillin (1: 14) dry syrup in the treatment of children with acute bacterial rhinosinusitis].

To demonstrate clinical value of clavulanic acid/amoxicillin (CVA/AMPC) 1:14 combination dry syrup for acute bacterial rhinosinusitis (ABRS), the efficacy and safety were evaluated in a multicenter, open-label, uncontrolled study in 27 children with ABRS. The proportion of subjects who were 'cured' at the test of cure as the primary endpoint was 88.5%. In subjects with a major pathogenic bacteria at baseline (i.e., Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis) bacterial eradication was achieved in ≥ 80% of the subjects with the exception of ß-lactamase non-producing ampicillin resistant H. influenzae: BLNAR and ß-lactamase producing ampicillin resistant H. influenzae: BLPAR (ß-lactamase producing amoxicillin/clavulanic acid resistant H. influenzae: BLPACR). The MIC of CVA/AMPC (1:14) was not higher than 4 µg/mL for all pathogens except one strain each of BLNAR and BLPAR (BLPACR). Drug-related adverse events were reported in 19% of patients (5/27 patients). All of the reported drug-related adverse events were classified as gastrointestinal disorders that have been commonly reported with antibacterial drugs. These results indicate that CVA/AMPC (1:14) was clinically useful for the treatment of ABRS and is also suggested that was effective especially for the treatment of ABRS in children caused by beta-lactamase-producing bacteria including M. catarrhalis.

Genetic characteristics of Haemophilus influenzae and Streptococcus pneumoniae isolated from children with conjunctivitis-otitis media syndrome.

Acute conjunctivitis is the most common ocular disorders among children and frequently concomitant with acute otitis media (AOM) as conjunctivitis-otitis syndrome. In this study, we evaluated prevalence of causative pathogens and PCR-based genotypes of Haemophilus influenzae and Streptococcus pneumoniae among children with conjunctivitis-otitis media syndrome. Nontypeable H. influenzae (NTHi) is identified most often at 61.8% in conjunctiva exudates followed by S. pneumoniae at 28.2% and Moraxella catarrhalis at 19.1%. Genetic ß-lactamase nonproducing ampicillin resistant (gBLNAR) strains of NTHi and genetic penicillin resistant S. pneumoniae (gPRSP) were identified at 72.1% and at 74.2% among conjunctiva isolates by polymerase chain reaction (PCR), respectively. Pneumococcal strains having either ermB or mefE genes were identified at 93.5% among conjunctiva isolates. The restriction fragment of patterns of 89.7% pairs of H. influenzae isolates and 100% pairs of pneumococcal isolates from conjunctiva exudates, middle ear fluids (MEFs) and nasopharyngeal swabs were identical. In contrast to the previous reports, most prevalent strains from conjunctivitis-otitis media syndrome was BLNAR H. influenzae in this study. The causative pathogen responsible for acute conjunctivitis will be originated from the nasopharynx. In the absence of MEFs one can possibly rely on the nasopharyngeal culture to guide an appropriate treatment.

An application of outer membrane protein p6-specific enzyme-linked immunosorbent assay for detection of haemophilus influenzae in middle ear fluids and nasopharyngeal secretions.

An enzyme-linked immunosorbent assay specific to outer membrane protein P6 (P6-ELISA) was applied for detecting Haemophilus influenzae in middle ear fluids (MEFs) from acute otitis media (AOM) patients and in nasopharyngeal secretions (NPSs) from acute rhinosinusitis patients. P6-ELISA had a sensitivity of 83.3% for MEFs and 71.5% for NPSs and a specificity of 85.6% for MEFs and 92.5% for NPSs, respectively. Real-time PCR exhibited significant differences in the number of ompP1 gene copies among samples determined by P6-ELISA to be positive and negative for H. influenzae. However, because the P6-ELISA test has the reactivity in Haemophilus species include two commensals H. haemolyticus and H. parainfluenzae, it is thus a weak method in order to detect only NTHi correctly. Consequently, diagnosis using the P6-ELISA should be based on an overall evaluation, including the results of other related examinations and clinical symptoms to prevent misleading conclusions in clinical setting.

Good transfer of tebipenem into middle ear effusion conduces to the favorable clinical outcomes of tebipenem pivoxil in pediatric patients with acute otitis media.

Tebipenem pivoxil, an oral carbapenem antibiotic for pediatric use, exhibits excellent clinical effects on acute otitis media (AOM). The present study was conducted to assess the pharmacokinetic profile of tebipenem in middle ear effusion and to examine the clinical efficacy of tebipenem pivoxil by calculating the values of the pharmacokinetic-pharmacodynamic parameters (AUC/MIC, C max/MIC, and T > MIC) of tebipenem at the site of action. Twenty-three pediatric outpatients diagnosed with AOM were enrolled. Ear discharge or nasopharyngeal swabs collected before the onset of oral administration were used to conduct bacteriological examinations, and subjects were then treated by twice-a-day oral administration of tebipenem pivoxil 6 mg/kg. The clinical isolates of Streptococcus pneumoniae and Haemophilus influenzae were obtained from 10 and 19 pediatric patients (8 overlapped), respectively. On day 2 of administration, blood and middle ear effusion were collected from 20 pediatric patients to measure plasma and middle ear concentrations of tebipenem. Consequently, the C max and the AUC0-∞ in plasma were 5.3 ± 1.6 µg/ml (mean ± SD) and 7.9 ± 0.2 µg h/ml, respectively. The C max in middle ear effusion of tebipenem was 1.2 ± 0.1 µg/ml, exceeding its MIC for these pathogens. The ratio of AUC0-∞ in middle ear effusion to AUC0-∞ in plasma was 0.36, showing the good transfer of tebipenem into the effusion; this result corroborated the known high rate of clinical efficacy of tebipenem pivoxil for patients with AOM and the low incidence of recurrence in them as manifested by the healing rate of 94.1 % (16/17).

Evaluation of a rapid immunochromatographic ODK-0901 test for detection of pneumococcal antigen in middle ear fluids and nasopharyngeal secretions.

Since the incidence of penicillin-resistant Streptococcus pneumoniae has been increasing at an astonishing rate throughout the world, the need for accurate and rapid identification of pneumococci has become increasingly important to determine the appropriate antimicrobial treatment. We have evaluated an immunochromatographic test (ODK-0901) that detects pneumococcal antigens using 264 middle ear fluids (MEFs) and 268 nasopharyngeal secretions (NPSs). A sample was defined to contain S. pneumoniae when optochin and bile sensitive alpha hemolytic streptococcal colonies were isolated by culture. The sensitivity and specificity of the ODK-0901 test were 81.4% and 80.5%, respectively, for MEFs from patients with acute otitis media (AOM). In addition, the sensitivity and specificity were 75.2% and 88.8%, respectively, for NPSs from patients with acute rhinosinusitis. The ODK-0901 test may provide a rapid and highly sensitive evaluation of the presence of S. pneumoniae and thus may be a promising method of identifying pneumococci in MEFs and NPSs.

Distribution of fibronectin-binding protein genes (prtF1 and prtF2) and streptococcal pyrogenic exotoxin genes (spe) among Streptococcus pyogenes in Japan.

Two hundred and seventy-two strains of Streptococcus pyogenes isolated from patients with invasive and noninvasive infections in Japan were evaluated for the prevalence of fibronectin-binding protein genes (prtF1 and prtF2). The possible associations of the genes with streptococcal pyrogenic exotoxin genes, macrolide resistance genes, and emm types were also evaluated. Overall, about 50% of S. pyogenes isolates carried fibronectin-binding protein genes. The prevalence of the prtF1 gene was significantly higher among isolates from noninvasive infections (71.4%) than among isolates from invasive infections (30.8%; P = 0.0037). Strains possessing both the prtF1 and prtF2 genes were more likely to be isolates from noninvasive infections than isolates from invasive infections (50.6% vs 15.4%; P = 0.019). S. pyogenes isolates with streptococcus pyrogenic exotoxin genes (speA and speZ) were more common among isolates without fibronectin-binding protein genes. The speC gene was more frequently identified among isolates with fibronectin-binding protein genes (P = 0.05). Strains belonging to emm75 or emm12 types more frequently harbored macrolide resistance genes than other emm types (P = 0.0094 and P = 0.043, respectively). Strains carrying more than one repeat at the RD2 region of the prtF1 gene and the FBRD region of the prtF2 gene were more prevalent among strains with macrolide resistance genes than among strains negative for macrolide resistance genes. These genes (i.e., the prtF1, prtF2, and spe genes) may enable host-bacteria interaction, and internalization in the host cell, but may not enable infection complications such as invasive diseases.

Serotype distribution and penicillin resistance of Streptococcus pneumoniae isolates from middle ear fluids of pediatric patients with acute otitis media in Japan.

Out of 175 pneumococcal isolates from middle ear fluids, 26.3% were penicillin-resistant S. pneumoniae (PRSP). Serotypes 19F and 23F occurred most frequently among PRSP strains. The 7-valent pneumococcal conjugate vaccine (PCV) showed better coverage of PRSP strains (87.0%). The 7-valent PCV may reduce the prevalence of PRSP in Japan.

Clinical effectiveness of ototopical application of mupirocin ointment in methicillin-resistant Staphylococcus aureus otorrhea.

OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) otorrhea has become an increasing problem with regard to infection through the tympanic membrane perforation and postsurgical infection. In particular, dry ear, at the preoperative stage, is considered to be a crucial factor in surgery. We evaluated how to control MRSA otorrhea before and after ear surgery. PATIENTS AND METHODS: Twenty-six patients having MRSA otorrhea were enrolled in the present study and randomly divided into 2 groups, namely, mupirocin ointment therapy for 16 patients and ofloxacin ear drops for 10 patients. Approximately 0.6 mg of mupirocin ointment was administered locally to the tympanic membrane and the promontory around and through the perforation with its adjacent external ear canal 1 to 4 times for 2 or 3 weeks at the clinic. On the other hand, ofloxacin ear drops were administered daily by the patients for 2 or 3 weeks at home. RESULTS: Complete elimination of MRSA from the ear was obtained in all patients of the mupirocin group. This showed a significant improvement (p < 0.001) as compared with the ofloxacin group (improvement + cure rate, 40%). Local application of mupirocin did not aggravate hearing acuity of any patients who were evaluated by pure-tone audiometry before and after treatment. CONCLUSION: The present findings first indicate that minimally essential application of mupirocin ointment is an extremely useful ototopical agent against MRSA otorrhea without ototoxicity.

[Efficacy and safety of potassium clavulanate/amoxicillin (CLAVAMOX) dry syrup in children with otitis media].

To evaluate the efficacy and safety of CLAVAMOX dry syrup (potassium clavulanate/amoxicillin) in children with otitis media, we conducted a postmarketing surveillance from February to September 2006. The analysis was made on the basis of 470 survey sheets collected from 127 medical institutions, of which we investigated 455 cases for safety, and 433 cases for efficacy. The efficacy was 95.2% in the 433 subjects eligible for the efficacy analysis. The clinical improvement rates for major symptoms (otalgia, otorrhea, flare reaction of drum membrane and fever) were 95% or more. The efficacies for the three major offending bacteria of otitis media (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were between 94.6% and 100%. The efficacies for penicillin-resistant Streptococcus pneumoniae (PRSP) and penicillin intermediate resistant Streptococcus pneumoniae (PISP) were 95% or more. Adverse drug reactions (ADRs) were reported in 106 (23.3%) of the 455 subjects eligible for safety analysis. The major ADRs were diarrhea, of which incident was 22.6% (103 of 455). These ADRs were observed at a higher rate in younger age patients. Most of the diarrhea cases were non-serious, reversible on discontinuation or continuation of the drug. No clinically important serious diarrhea cases such as pseudomembranous colitis or dehydration were observed. Our surveillance results demonstrated that CLAVAMOX dry syrup had excellent efficacy and clinically manageable safety in children with otitis media. These findings indicated that this medicine was clinically-useful in children with otitis media.

[Epidemiological survey of pneumococcus serotypes in pediatric patients with acute suppurative otitis media].

To determine the distribution of Streptococcus pneumoniae serotypes isolated from patients under 6 years of age with acute suppurative otitis media, to calculate the serotype coverage of 7-valent pneumococcal conjugate vaccine, and to clarify trends in PCG-resistant Streptococcus pneumoniae, we conducted a one-year prospective study from April 2005 to March 2006 at 10 medical institutions in Hokkaido, Miyagi, Chiba, Tokyo, Kanagawa, and Mie, Japan. Specimens collected by tympanotomy or myringotomy numbered 856, and 691 strains were isolated from 599 specimens. Of these, 219 isolates (31.7%) were identified as Streptococcus pneumoniae and 201 met study requirements. The most common serotype was 19F (52 isolates, 25.9%), followed by 6B (30 isolates, 14.9%) and 23F (24 isolates, 11.9%). Seven-valent vaccine serotype coverage was 62.7%. The percentage of PSSP was 40.3%, PISP 42.8%, and PRSP 16.9%, resistant strains (PISP and PRSP) combined accounted for 59.7%. Seven-valent vaccine serotype coverage for PISP was 80.2% and PRSP 82.4%. PBP gene mutation was observed in 175 isolates (87.1%), including 70 of gPISP (34.8%) and 105 of gPRSP (52.2%). Gene mutation induced by macrolides was found in 176 isolates (87.6%).

Molecular analysis of intrafamiliar transmission of Moraxella catarrhalis.

The possible intrafamiliar transmission of Moraxella catarrhalis was evaluated in 3 pairs between children and their parents, and 8 pairs between siblings from 11 families. Of the 22 isolates, all were found producing beta-lactamase. Molecular typing by pulsed-field gel electrophoresis (PFGE) with Not I and Spe I showed that the PFGE patterns in 2 of 3 pairs between children and their parents, and 4 of 8 pairs between siblings were indistinguishable and those of the remaining pairs were different. These data indicate a possible high rate of intrafamiliar transmission of M. catarrhalis.

Macrolide-resistant genes of Streptococcus pyogenes isolated from the upper respiratory tract by polymerase chain reaction.

The growing number of macrolide-resistant strains of Streptococcus pyogenes is an increasing problem worldwide. This study evaluated 300 clinical isolates obtained from the upper respiratory tract. Minimal inhibitory concentrations (MICs) of erythromycin (EM), azithromycin (AZM), and clindamycin (CLDM), serotypes, and macrolide resistance genes of mefA, ermB, and ermTR were determined. The genetic relationship of EM-resistant and susceptible strains were also analyzed by pulsed-field gel electrophoresis (PFGE). Twenty-nine (9.7%) EM-resistant S. pyogenes were identified. Of the 29 strains showing resistance to EM, 22 isolates (7.3%, MIC 3.13-12.5 microg/ml) expressed the mefA gene. The predominant serotypes among the mefA-positive isolates were T12, emm9 or T25, emm75-1. The two isolates (0.1%) that possessed the ermB gene were highly resistant to EM (MIC > 100 microg/ml). The remaining five strains (1.6%) possessed the ermTR gene (MIC 3.13-100 microg/ml). Restriction fragment polymorphism analyzed by pulsed-field gel electrophoresis (PFGE) by SmaI and ApaI digestions showed several clones among the mefA-positive S. pyogenes. Our findings suggest that the mefA gene is the predominant mechanism for macrolide resistance and that this gene is horizontally transmitted among M phenotype strains of S. pyogenes. Consequently, macrolides would not be the first drug of choice for treatment of tonsillitis and other S. pyogenes-related diseases. Physicians and researchers need to take into consideration the macrolide resistance of some strains of S. pyogenes.

Possible high rate of transmission of nontypeable Haemophilus influenzae, including beta-lactamase-negative ampicillin-resistant strains, between children and their parents.

The possible transmission of nontypeable Haemophilus influenzae between children and their parents was evaluated in 18 pairs of subjects from 15 families. Of the 33 isolates, 31 were found to be beta-lactamase negative, including 10 beta-lactamase-negative, ampicillin (AMP)-resistant (BLNAR) strains (AMP MIC, >or=1.0 microg/ml) and 2 were beta-lactamase producing. Molecular typing by pulsed-field gel electrophoresis (PFGE) showed that 10 BLNAR isolates had 6 patterns, 23 non-BLNAR isolates had 13 patterns, and these patterns were different from each other, except for 1 pattern. As a result, the PFGE patterns in 14 of 18 pairs were indistinguishable and those in 4 pairs were different. These data indicate a possible high rate of intrafamilial transmission of nontypeable H. influenzae, including BLNAR strains, between children and their parents.

High rate of transmission of penicillin-resistant Streptococcus pneumoniae between parents and children.

Transmission of Streptococcus pneumoniae between children and their parents was evaluated in 29 pairs from 25 families. The serotypes of 35 pneumococcal isolates from 18 (62.1%) of 29 child-parent pairs were identical. Of the 35 isolates, 23 showed intermediate resistance and 10 were fully resistant to penicillin G. PCR indicated that all 35 strains had at least one alteration in penicillin-binding protein genes pbp1a, pbp2x, and pbp2b and 33 strains had macrolide resistance genes mef(A) and/or erm(B). As a result, the PCR patterns of 16 of 18 pairs were identical. Molecular typing by pulsed-field gel electrophoresis showed that 12 pairs were indistinguishable, 3 pairs were closely related, 2 pairs were possibly related, and only one pair was different. Our data indicate the presence of a high rate of transmission of penicillin-resistant S. pneumoniae between children and their parents.