Yoshitake Sato

Nationwide survey of the development of drug-resistance in the pediatric field: drug sensitivity of Haemophilus influenzae in Japan

We evaluated the β-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 β-lactamase-negative ampicillin (ABPC)-susceptible (BLNAS) strains declined from 62.9% to 34.3%; the proportions of β-lactamase-positive ABPC-resistant (BLPAR) strains were 8.3% and 6.4% in phases 1 and 2, but the proportion of β-lactamase-negative ABPC-resistant (BLNAR) strains increased from 28.8% in phase 1 to 59.3% in phase 2. Comparison of the MIC90 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 MIC90 values of the β-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 β-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.

Nationwide survey of the development of drug-resistant pathogens in the pediatric field in 2007 and 2010: drug sensitivity of Streptococcus pneumoniae in Japan (second report).

We previously conducted nationwide surveillance of Streptococcus pneumoniae in 2000–2001 (period 1) and 2004 (period 2) and reported the findings. Subsequent surveillance surveys conducted in 2007 (period 3) and 2010 (period 4) are now reported. Bacterial strains were clinically isolated from children with meningitis, sepsis, and respiratory tract infections at 27 hospitals participating in the Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease. Twenty-one drugs were investigated for 283 isolated strains in period 3, and 24 drugs were investigated for 459 strains in period 4. In period 3, 43.8xa0% of strains were penicillin-susceptible S. pneumoniae (PSSP), 52.3xa0% were penicillin-intermediate S. pneumoniae (PISP), and 3.9xa0% were penicillin-resistant S. pneumoniae (PRSP). In period 4, the percentages were PSSP 23.1xa0%, PISP 49.9xa0%, and PRSP 27.0xa0%. The resistance rates were 56.2xa0% and 76.9xa0%, respectively. Drug sensitivity was best with panipenem, at a minimum inhibitory concentration (MIC)90 ≤0.063xa0μg/ml in period 3, and with tebipenem (MIC90xa0≤xa00.063xa0μg/ml) in period 4. Patients’ background factors related to increased bacterial resistance were investigated, and significant differences were found depending on whether a child had siblings (Pxa0=xa00.0056) or was a daycare center attendee (Pxa0=xa00.0195) in period 3, and age category (Pxa0=xa00.0256) in period 4. No factors were common to both periods 3 and 4. Pneumococcus is a major causative organism of pediatric infectious disease, and we plan to continue conducting surveillance and providing information in the future.

Pharmacokinetics of antibiotics in neonates

The pharmacodynamics in neonates are different from those in adults and children because the absorption, distribution, metabolism and excretion of drugs in neonates are always changing for the following reasons. In neonates, the proportion of extracellular fluid is large; the amount of plasma protein is small; renal function is immature; and the hepatic enzyme system is immature. In addition, individual birthweights, gestational ages in weeks, cardiopulmonary functions and renal excretory functions vary. All of these factors should be considered when selecting the dose and administration method of a drug. In concrete terms the distribution volume is large, which causes a low maximum concentration. In addition neonate renal excretory function is low and the hepatic enzyme system is immature, thus the half‐life of drugs is prolonged. Therefore, the same dose per unit time as that for children (including infants) needs to be administered to neonates at dosing intervals that may be prolonged according to renal function.

A practical approach estimating etiologic agents using real-time PCR in pediatric inpatients with community-acquired pneumonia

To evaluate pathogens in pediatric inpatients with community-acquired pneumonia (CAP), an Acute Respiratory Diseases Study Group organized by ten Japanese medical institutions devised a rapid, reliable process based on real-time PCR results in nasopharyngeal swab samples plus admission blood test results. From April 2008 to April 2009, we enrolled 903 children with CAP based on chest radiographs and clinical findings who were hospitalized within 5xa0days of onset. Comprehensive real-time PCR was used to detect 6 bacteria and 11 respiratory viruses. The swab specimens also were used for bacterial cultures. After initial determination of presence or absence of viral and mycoplasmal infections, significant bacterial contributions were defined by bacterial identification, clinical efficacy of antimicrobial agent, and reference to blood test results. Children were stratified by age: below 1xa0year, 1xa0year, 2–5xa0years, or at least 6xa0years old. Among patients studied, 34.4xa0% were diagnosed with viral infection; 21.8xa0%, bacterial infection; 17.5xa0%, viral/bacterial co-infection; 5.9xa0%, mycoplasmal infection; 0.3xa0%, mycoplasmal/bacterial co-infection; and 1.7xa0%, viral/mycoplasmal co-infection. The remaining 18.4xa0% had unknown pathogens. Purely viral infection was suggested mainly in infants younger than 1xa0year; mycoplasmal infection typically occurred in children at least 6xa0years old. Our results suggest usefulness of real-time PCR for nasopharyngeal samples together with blood tests in estimating etiologic agents in clinical settings.

Nationwide survey of the development of drug resistance in the pediatric field in 2000-2001, 2004, 2007, 2010, and 2012: evaluation of the changes in drug sensitivity of Haemophilus influenzae and patients' background factors.

The Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease has conducted surveillance of pediatric patients with respiratory tract infections, meningitis, and sepsis five times (in 2000-2001 [period 1], 2004 [period 2], 2007 [period 3], 2010 [period 4], and 2012 [period 5]). With respect to the clinically isolated Haemophilus influenzae, the drug susceptibility, the frequency of drug-resistant strains, and patients background factors in each period have already been reported. Here we evaluate trends in the development of drug resistance in H. influenzae, and the relationship between the development of drug resistance and patients background factors in the aforementioned five periods. H. influenzae derived from pediatric patients with respiratory tract infections that had been previously collected (period 1, 448 isolates; period 2, 376 isolates; period 3, 386 isolates; period 4, 484 isolates; and period 5, 411 isolates) were analyzed. The proportions of ß-lactamase-nonproducing ampicillin (ABPC)-intermediate resistant (BLNAI) strains + β-lactamase-nonproducing ABPC-resistant (BLNAR) strains were 28.8% in period 1, 59.3% in period 2, 61.1% in period 3, 58.1% in period 4, and 63.5% in period 5, showing a rapid increase from period 1 to period 2 followed by an almost constant rate of approximately 60%. The proportion of ß-lactamase-producing ABPC-resistant (BLPAR) strains + ß-lactamase-producing clavulanic acid/amoxicillin-resistant (BLPACR) strains was 4.4% in period 3, which was somewhat low; however, there were no significant changes in the proportions of these strains, which ranged between 6.4% and 8.7% throughout the surveillance period except for period 3. The drugs whose MIC90 values against BLNAR strains were low throughout the surveillance included piperacillin (0.25 μg/mL) and tazobactam/piperacillin (0.125-0.25 μg/mL) in the penicillins; cefditoren and ceftriaxone (0.25-0.5 μg/mL for both) in the cephems; meropenem (0.5-1 μg/mL) and tebipenem (1 μg/mL) in the carbapenems; and levofloxacin, tosufloxacin, and garenoxacin (≤ 0.06 μg/mL for all) and norfloxacin (0.06-0.125 μg/mL) in the quinolones. We investigated the relationship between the frequency of BLNAS strains/BLNAI + BLNAR strains and patients background factors in each surveillance period. Significant differences were shown on age category (< 3 years or ≥ 3 years) in all periods except period 4, and the presence/absence of prior administration of antimicrobial agents within one month in period 2 and period 3. In all periods, the frequency of BLNAI + BLNAR strains were higher in patients aged < 3 years than in patients aged ≥ 3 years, and were also higher in patients with presence of prior treatment than in patients without prior treatment. We consider that it is important to promote the proper use of antimicrobial agents by conducting surveillance continuously in the future to clarify the relationship between the development of drug resistance in H. influenzae and patients background factors and provide those information to clinical setting.

Results of a multicenter survey of diagnosis and treatment for bacterial meningitis in Japan.

An evaluation committee was organized to evaluate 464 cases of bacterial meningitis treated at 108 nationwide medical facilities participating in this survey between April 2004 and January 2007. There were 413 evaluable cases of bacterial meningitis, including 342 children (82.8%) and 71 adults (17.2%). Haemophilus influenzae (217 cases, 63.5%) and Streptococcus pneumoniae (35 cases, 49.3%) were the most frequent pathogens for meningitis in children and adults, respectively. The most used initial therapy for children was carbapenemxa0+xa0cephalosporin therapy (212 cases, 61.9%). Of the 333 children included in efficacy evaluation, 320 (96.1%) were rated as remission, 10 (3.0%) as partial remission, and three (0.9%) as poor response. The combination therapy with two drugs was also most often used in adults (41 cases, 57.7%). In efficacy analysis in 60 adults, remission was observed in 50 (83.3%), partial remission in five (8.3%) and poor response in five (8.3%). In prognosis analysis, 273 (80.3%) among 340 children were alive at the end of treatment without sequelae, but one (0.3%) died by the end of treatment, and 64 (18.8%) had sequelae. Of all adults, six (8.5%) died of bacterial meningitis and 23 (32.4%) had sequelae at the end of treatment. Among the patients followed up for 1xa0year, 26 (12.3%) of 211 children and three (7.7%) of 39 adults had sequelae. The selection of drugs and its dose level of many cases were appropriate, but the dose level of several cases was inappropriate. It is necessary to spread the method of proper antibiotic therapy.

Recent trends in pediatric bacterial meningitis in Japan – A country where Haemophilus influenzae type b and Streptococcus pneumoniae conjugated vaccines have just been introduced

To investigate the trends in incidence and the characteristics of bacterial meningitis in Japan where Haemophilus influenzae type b (Hib) vaccine and 7-valent pneumococcal conjugated vaccine (PCV7) were introduced in 2008 and 2010, respectively, which was 5-20 years after their introduction in western countries. The nationwide Japanese survey of pediatric and neonatal bacterial meningitis was performed in 2011 and 2012. We analyzed the epidemiological and clinical data, and compared the information obtained in the previous nationwide survey database. We also investigated the risk factors for disease outcome. In the 2011-2012 surveys, 357 patients were evaluated. H. influenzae, Streptococcus pneumoniae, Streptococcus agalactiae and Escherichia coli were the main organisms. The number of patients hospitalized with bacterial meningitis per 1000 admissions decreased from 1.31 in 2009 to 0.43 in 2012 (p < 0.001). The incidence of H. influenzae and S. pneumoniae meningitis also decreased from 0.66 to 0.08 (p < 0.001), and 0.30 to 0.06 (p < 0.001), respectively. Only 0-2 cases with Neisseria meningitidis were reported each year throughout 2001-2012. The median patient age was 10-12 months in 2001-2011, and became lower in 2012 (2 month old) (p < 0.001). The fatality rate for S. agalactiae is the highest (5.9% (11/187)) throughout 2001-2012 among the four organisms. Risk factors for death and sequelae were convulsions at onset, low CSF glucose, S. agalactiae etiology, and persistent positive CSF culture. Hib vaccine and PCV7 decreased the rate of bacterial meningitis. Earlier introduction of these vaccines may have prevented bacterial meningitis among Japanese children.

Genetic analysis of a pediatric clinical isolate of Moraxella catarrhalis with resistance to macrolides and quinolones

During the surveillance conducted in 2012 by the Drug-resistant Pathogen Surveillance Group in Pediatric Infectious Disease, we isolated a strain of Moraxella catarrhalis that demonstrated resistance to both macrolides and quinolones from a male pediatric patient aged 1.5 years who had developed acute bronchitis. Then we evaluated the susceptibility of this strain to different types of antibacterial agents and conducted a genetic analysis. The results of the susceptibility evaluation showed that the MIC values of azithromycin, clarithromycin, and rokitamycin were >64 μg/mL, >64 μg/mL, and 4 μg/mL, respectively; clearly demonstrating resistance to macrolides. The MIC values of the quinolones levofloxacin, tosufloxacin, and garenoxacin were 4 μg/mL, 2 μg/mL, and 1 μg/mL, respectively; indicating decreased susceptibility. The genetic analysis of this strain revealed one mutation in 23s rRNA with a replacement of adenine by thymine at nucleotide position 2330 (A2330T) and another mutation in gyrB at nucleotide position 1481 by replacement of adenine with guanine (A1481G) that caused a substitution of the 494 th asparagine acid by glycine, as being associated with the observed resistance to macrolides and quinolones, respectively. Similar to drug-resistant bacteria Streptococcus pneumoniae and Haemophilus influenzae, the prevalence of which has recently increased, the treatment of drug-resistant M. catarrhalis infections is considered difficult due to the development of resistance to different types of antibacterial agents. It is vital to maintain an unwavering focus on the trend toward an increasing number of drug-resistant M. catarrhalis strains and ensure the proper use of each antibacterial agent.

Nationwide survey of the development of drug-resistant pathogens in the pediatric field: drug sensitivity of Streptococcus pneumoniae in Japan.

We evaluated the resistance to 20 different antibacterial agents of 362 clinically isolated strains of Streptococcus pneumoniae accumulated from October 2000 to July 2001 (phase 1) and of 332 different strains accumulated from January to June 2004 (phase 2), from institutions throughout Japan that participated in the surveys carried out by the Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease. In phase 1, the proportions of penicillin-sensitive S. pneumoniae (PSSP), penicillin-insensitive S. pneumoniae (PISP), and penicillin-resistant S. pneumoniae (PRSP) were 35.4%, 34.8%, and 29.8%, respectively, and the proportions were almost the same in phase 2: 33.1%, 37.0%, and 29.8%, respectively. Comparison of the MIC90 values of the antibacterial agents for PRSP in phase 1 and phase 2 revealed that these values for cefditoren, cefpodoxime, cefdinir, faropenem, ceftriaxone, cefotaxime, meropenem, and vancomycin increased by twofold to fourfold during the 3 years between phase 1 and phase 2. However the MIC90 of rokitamycin increased more than fourfold. The proportion of S. pneumoniae that were PISP + PRSP remained almost constant over the 3 years between phase 1 and phase 2. The background factors of patient age, previous administration of antibacterial agents, and attendance at a day nursery were examined; we found that in phase 1, the proportion of PISP + PRSP was significantly higher than that of PSSP in patients under 4 years old who had previously received antibacterial agents, but no significant differences were found in any of these background factors in the phase 2 survey. No significant difference was found in the proportions of penicillin-resistant bacteria according to whether or not the child had attended a day nursery.

Nationwide survey of Streptococcus pneumoniae drug resistance in the pediatric field in Japan

Streptococcus pneumoniae is a major causative pathogen of pneumonia in children. The Drug‐Resistant Pathogen Surveillance Group in Pediatric Infectious Disease conducted a nationwide surveillance of S. pneumoniae in 2000–2001, 2004, 2007, 2010 and 2012, and investigated changes in drug resistance of S. pneumoniae.