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During the period from January to December 2015, 104 Streptococcus pneumoniae strains, 129 Haemophilus influenzae strains and 54 Moraxella catarrhalis strains isolated from clinical specimens of pediatric infections in the national 16 institutions, studied susceptibilities of total 28 antibiotics, the capsular serotype for S. pneumoniae, the capsular b type and β-lactamase production capability for H. influenzae, and the β-lactamase production capability for M. catarrhalis were measured. In S. pneumoniae, the results showed that 68 strains (65.4%) were PSSP, 32 (30.8%) were PISP, and 4 (3.8%) were PRSP. The susceptibilities of TBPM and GRNX among oral antibiotics, and PAPM among injectable antibiotics demonstrated the lowest value with MIC90 ≤ 0.06 μg/mL. The most frequent distribution of S. pneumoniae serotypes was seen in 15B, followed by 19A, and 35B. Serotype strains contained in 13-valent pneumococcal conjugate vaccine (PCV13) were 19 strains (18.3%). In H. influenzae, the results showed that BLNAS accounted for 40 strains (31.0%), BLNAI for 28 strains (21.7%), BLNAR for 47 strains (36.4%), β-lactamase producing for 14 strains (10.8%). The susceptibilities of quinolones demonstrated the lowest outcome among oral antibiotics with MIC90 ≤ 0.06 μg/mL, and CTRX and TAZ/PIPC (TAZ4 fixed) among injectable antibiotics with MIC of 0.25 μg/mL. There was no detection of capsular type b strains. In M. catarrhalis, all the isolates were β-lactamase producing strains. The susceptibilities of TBPM, CPFX, TFLX and GRNX among oral antibiotics, and TAZ/PIPC (TAZ4 fixed), PAPM, MEPM and DRPM among injectable antibiotics demonstrated the lowest outcome with MIC of ≤0.06 μg/mL., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae are the main pathogens causing community-acquired pneumonia (CAP). We identified S. pneumoniae (n = 241), H. influenzae (n = 123), and M. pneumoniae (n = 54) as causative pathogens from clinical findings and blood tests from pediatric CAP patients (n = 903) between April 2008 and April 2009. Identification of genes mediating antimicrobial resistance by real-time PCR was performed for all isolates of these three pathogens, as was antibiotic susceptibility testing using an agar dilution method or broth microdilution method. The genotypic (g) resistance rate was 47.7 % for penicillin-resistant S. pneumoniae (gPRSP) possessing abnormal pbp1a, pbp2x, and pbp2b genes, 62.6 % for β-lactamase-nonproducing, ampicillin-resistant (gBLNAR) H. influenzae possessing the amino acid substitutions Ser385Thr and Asn526Lys, and 44.4 % for macrolide-resistant M. pneumoniae (gMRMP) possessing a mutation of A2063G, A2064G, or C2617A. Serotype 6B (20.3 %) predominated in S. pneumoniae, followed by 19F (15.4 %), 14 (14.5 %), 23F (12.0 %), 19A (6.2 %), and 6C (5.4 %). Coverage for the isolates by heptavalent pneumococcal conjugate vaccine (PCV7) and PCV13, respectively, was calculated as 68.5 and 80.9 %. A small number of H. influenzae were identified as type b (6.5 %), type e (0.8 %), or type f (0.8 %); all others were nontypeable. Proper use of antibiotics based on information about resistance in CAP pathogens is required to control rapid increases in resistance. Epidemiological surveillance of pediatric patients also is needed to assess the effectiveness of PCV7 and Hib vaccines after their introduction in Japan.

The minimum inhibitory concentation (MIC) and minimum bactericidal concentration (MBC) of 8 parental antibiotics were determined using 21 strains of Haemophilus influenzae from 21 children with invasive H. influenzae infection in 2006-2009. Children were from 4 months to 12 years, with 18 (85.7%) under 1 year old. Diagnosies involved meningitis or pneumonia in 7 (33.3%); epiglottitis, phlegmon, or arthritis in 2 each (9.5%), and occult bacteremia in 1 (4.8%). The capsule type was b (Hib) in 19 (90.5%). Classified by penicillin binding protein (PBP) gene mutation, strains were classified into (i) 6 beta-lactamase negative ampicillin resistant (BLNAR) (28.6%), (ii) 5 low-BLNAR (23.8%), (iii) 4 beta-lactamase positive clavulanic acid/amoxicillin resistant-II (19.0%), (iv) 2 beta-lactamase positive ampicillin resistant (9.5%), and (v) 4 beta-lactamase negative ampicillin susceptible (19.0%). Compared to a 2003-2005 survey, the number of sensitive strains had decreased significantly (p < 0.05). MIC90/MBC90 of ampicillin was 64/>128 microg/mL, piperacillin 16/>128 microg/mL, cefotaxime 0.5/0.5 microg/mL, ceftriaxone 0.12/0.12 microg/mL, panipenem 0.5/0.5 microg/mL, meropenem 0.12/0.12 microg/mL, doripenem 0.25/0.25 microg/ml, and chloramphenicil 1/2 microg/mL against H. influenza.

We evaluated the beta-lactamase-producing ability and resistance to 20 antibacterial agents of 448 clinically isolated strains of Haemophilus influenzae accumulated from October 2000 to July 2001 (phase 1) and of 376 different strains accumulated from January to June 2004 (phase 2), from institutions that participated in a nationwide Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease. Between phase 1 and phase 2 the proportion of beta-lactamase-negative ampicillin (ABPC)-susceptible (BLNAS) strains declined from 62.9% to 34.3%; the proportions of beta-lactamase-positive ABPC-resistant (BLPAR) strains were 8.3% and 6.4% in phases 1 and 2, but the proportion of beta-lactamase-negative ABPC-resistant (BLNAR) strains increased from 28.8% in phase 1 to 59.3% in phase 2. Comparison of the MIC(90) values of the antibacterial agents for H. influenzae in phase 1 and phase 2 showed that cefcapene, cefpodoxime, ceftriaxone, panipenem, and clarithromycin kept the same level, while cefdinir, faropenem, and rokitamycin showed 2-fold to 8-fold decreases. With the exception of the above antibiotics, all of the other antibacterial agents tested showed 2-fold to 4-fold increases. The MIC(90) values of the beta-lactam drugs for BLNAR were 2-fold to 32-fold higher than the values for BLNAS. The proportion of BLNAR H. influenzae strains rose dramatically over the 3 years between phases 1 and 2. In relation to age, prior administration of antibacterial agents, and attendance at a day nursery as background factors, no significant differences between BLNAS and BLNAR were detected in phase 1. In the phase 2 survey, the proportion of BLNAR strains showed significant differences between children under 3 years and those aged 3 years or more, and there were also significant differences according to whether antibacterial agents, especially beta-lactams, had been administered previously. No significant difference was found in resistant bacteria according to whether or not a child had attended a day nursery.

We examined the frequency of ampicillin (ABPC) resistance of 3784 strains of Haemophilus influenzae isolated from the infants aged from 1 month after birth to 12 years who had been treated in the Pediatric Department of our hospital for 9 years and 6 months from July 1999 to December 2008. We determined the drug susceptibility by Etest, and judged the resistance by the standard of Clinical and Laboratory Standard Institute. The rate of strains of MIC of less than 2 microg/ml to ABPC was 87.1% in 1999, but the ratio was decreasing year after year significantly up to 28.7% in 2008 (p < 0.001). beta-lactamase negative ABPC resistant (BLNAR) strains whose MIC to ABPC was more than 4 microg/ml was 2.9% in 1999, but increased significantly to 43.3% in 2008 (p < 0.001). MIC90 was 2 microg/ml in 1999, but increased to 16 microg/ml in 2008.

We evaluated 52 children with invasive Haemophilus influenzae infection in Kamikawa subprefucture, Hokkaido, Japan between 1996 and 2005. The most frequent disease was meningitis, in 30 children (57.7%), followed by pneumonia in 9 (17.3%), bacteremia in 8 (15.4%), epiglottitis in 4 (7.7%), and cellulitis in 1 (1.9%). Patients ranged in age from 0 days to 8 years. Thirty (57.7%) of the patients were less than 2 years old. Only 6 cases of invasive H. influenzae infection occurred in children older than 5 years. Between 1996 and 2005 the annual incidence rates of invasive H. influenzae infection in children aged less than 5 years, and those aged from 5 to 9 years were 4.3/100,000 to 56.8/100,000 and 0/100,000 to 12.4/100,000, respectively. A marked increase of the annual incidence rate in children aged under 5 years was observed in the most recent 2 years (2004 and 2005). No patients with invasive H. influenzae infection died, but sequelae were seen at discharge in 2 patients with meningitis, predominantly epilepsy and developmental delay of varying severity. Two patients with epiglottitis were treated by endotracheal intubation or tracheostomy. Of 41 strains isolated from 1999 to 2005, 35 were classified for antimicrobial resistance by the polymerase chain reaction (PCR) method. The number of strains of beta-lactamase-negative ampicillin-susceptible, low beta-lactamase-negative ampicillin-resistant, beta-lactamase-negative ampicillin-resistant, beta-lactamase-negative amoxicillin/clavulanic acid resistant-I, and beta-lactamase-positive amoxicillin/clavulanic acid resistant-II, were 22, 3, 5, 2, and 3, respectively. The serotype in 37 (97.4%) of 38 cases demonstrated type b.

A total of 16 isolates of Streptococcus pneumoniae and 18 isolates of Haemophilus influenzae were obtained from the blood of children admitted to the pediatric wards of hospitals in Hokkaido Kamikawa subprefecture between January 2003 and December 2005. The ages of the patients with S. pneumoniae or H. influenzae infection ranged from 2 months to 9 years and from 1 month to 4 years, respectively. The diagnoses of S. pneumoniae infection were as follows: pneumonia in 8 patients, occult bacteremia in 5 patients, and meningitis in 3 patients. The diagnoses of H. influenzae were: meningitis in 6 patients, pneumonia in 4 patients, occult bacteremia in 4 patients, epiglotitis in 2 patients, and facial cellulitis in 2 patients. Out of 16 S. pneumoniae isolates, penicillin-resistant strains with a mutation of 3 genes were observed in 7 children, and penicillin intermediate-resistant strains with a mutation of 1 or 2 genes were observed in 8 children. Out of 18 H. influenzae isolates, the beta-lactamase-negative ampicillin-resistant strain with a substitution of 2 points in the ftsI gene was revealed in 2 children, the beta-lactamase-negative ampicillin-resistant strain with a substitution of 1 point in the ftsI gene was observed in 4 children, the beta-lactamase-positive amoxicillin/clavulanic acid-resistant strain with blaTEM-1 and ftsI with 2 substitutions in the ftsI gene was observed in 3 children, and the beta-lactamase-positive ampicillin-resistant strain with blaTEM-1was not observed. The MBC90s of ampicillin, ceftriaxone, cefotaxime, meropenem, panipenem, and vancomycin against S. pneumoniae were 8 microg/ml, 1 microg/ml, 1 microg/ml 1 microg/ml, 0.25 microg/ml, and 0.5 microg/ml, respectively. Those of ampicillin, piperacillin, ceftriaxone, cefotaxime, meropenem, and panipenem against H. influenzae were >128 microg/ml, >128 microg/ml, 0.25 microg/mL, 1 microg/ml, 0.12 microg/ml, and 0.5 g/ml, respectively. It is suggest that the minimum bactricidal concentration (MBC) was dissociated from the minimum inhibitory concentration (MIC) in S. pneumoniae and H. influenzae with abnormal pbp genes.

Fifty isolates of Streptococcus pneumoniae and 42 isolates of Haemophilus influenzae were isolated from the blood of children admitted to pediatric wards of hospitals in subprefucture between January 1998 and December 2005. The susceptibilities were measured by a microbroth dilution method using a standard broth and a broth containing 4.5% albumin. Against S. pneumoniae, penicillin G, ampicillin, cefotaxime, ceftriaxone, panipenem, meropenem, vancomycin, cefditoren, cefcapene, cefteram, faropenem and tebipenem were used and against H. influenzae, ampicillin, piperacillin, cefotaxime, ceftriaxone, panipenem, meropenem, clavulanic acid/ amoxicillin, cefditoren, cefcapene, cefteram, faropenem and tebipenem were used. Against S. pneumoniae, tebipenem was the highest antimicrobial activity in oral antibiotics (MIC90; < or = 0.06 microg/ml) and panipenem showed the highest activity for intravenous antibiotics (MIC90; < or = 0.12 microg/ml). Against H. influenzae, cefditoren was the highest activity for oral antibiotics (MIC90; < or = 0.06 microg/ml) and meropenem showed the highest activity for intravenous antibiotics (MIC90; < or = 50.06 microg/ml). The MIC90s measured by albumin containing broth were higher than those measured by standard broth. Protein binding rates of ceftriaxone, cefditoren, and faropenem were greater than 90%, and the MIC90 of these antibiotics measured by albumin addition methods were over 4-fold higher than those measured by standard methods.

Between April 2001 and March 2003, we studied minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) of 7 strains of Streptococcus pneumoniae and 8 strains of Haemophilus influenzae isolated from children with meningitis. The age range of the patients was from 4 months to 5 years. Susceptibilities of ampicillin (ABPC), cefotaxime (CTX), panipenem (PAPM), and vancomycin (VCM) in S. pneumoniae and those of ABPC, CTX, ceftriaxone (CTRX), and meropenem (MEPM) in H. influenzae were measured. MICs of ABPC, CTX, PAPM, and VCM to S. pneumoniae were < or = 0.06-2, < or = 0.06-0.5, < or = 0.06, and 0.25-0.5 microgram/ml and MICs of ABPC, CTX, CTRX, and MEPM to H. influenzae were 0.12-64, < or = 0.06-0.5, < or = 0.06-0.12, and < or = 0.06-0.25 microgram/ml, respectively. In 5 of all strains, difference between MIC and MBC to ABPC was observed. Four strains out of them had mutations of penicillin binding protein genes measured by PCR methods.

Between September 1999 and August 2001, we studied serotypes to capsular antigen, beta-lactamase production, mutation of penicillin binding protein (PBP) genes by PCR method, and antimicrobial susceptibilities of 13 strains of Haemophilus influenzae isolated from spinal fluid or blood in children. Diseases of patients were meningitis in 11, pneumonia in 1, and laryngitis in 1. The age range of the patients was from 26 days to 5 years. The serotypes of all strains were b. Four of the 13 strains were beta-lactamase-positive. The mutation of genes of pbp3 was revealed from 4 isolates and 2 of the strains were beta-lactamase-positive. MICs of ampicillin to beta-lactamase-negative strains ranged from 0.125 to 1 microgram/ml and those to beta-lactamase-positive were more than 32 micrograms/ml. MICs of 2 strains of beta-lactamase-negative and mutation-positive were 0.5 and 1 microgram/ml. The excellent active antimicrobials in our study was cefotaxime (MIC90 0.06 microgram/ml), meropenem (MIC90 0.125 microgram/ml), ceftazidime (MIC90 0.25 microgram/ml), and cefepime (MIC90 0.25 microgram/ml).

We evaluated 24 children with invasive Haemophilus influenzae infections between 2006 and 2015 in Kamikawa subprefecture of Hokkaido, Japan. The most frequent disease was pneumonia in 12 cases (50.0%), followed by meningitis in 7 (29.2%) and bacteremia in 5 (20.8%). Patients ranged in age from 3 months to 12 years of age. Seventeen (70.8%) of the total were less than 2 years old. The incidence rate of H. influenzae infection varied from 15.1 to 36.3 per 100,000 population in the Kamikawa area during the period from 2006 through 2011. The corresponding rate decreased to 10.4 per 100,000 population in 2012, and there were no cases after 2013. Meningitis occurred in 1–2 patients annually from 2006 to 2011, showing an incidence rate of 4–10 per 100,000 population per year, while no cases were reported during or after 2012. No patients with invasive H. influenzae infection died, but sequelae were seen at discharge in 1 patient with meningitis, that had hydrocephalus and developmental delay. In Japan, introduction of the H. influenzae type b (Hib) vaccine was in November 2008. Initially, this vaccination was voluntary, resulting in a low vaccination rate. According to the national policy, and the self-pay burden for vaccination was decreased in December 2010, and the vaccination rate increased markedly to over 90%. This report provides a meaningful demonstration that introduction of the Hib vaccine markedly reduced invasive H. influenzae infections, exerting a beneficial effect in Japan, as it has in the world. [ABSTRACT FROM AUTHOR]