[Pediatric bacterial meningitis prognosis and antibiotic treatment].

An evaluation committee studied the relationship between initial treatment drug and prognosis in 339 of 466 subjects with bacterial meningitis treated at 108 institutions between April 2004 and January 2007, after excluding those with uncertain diagnosis or non-assessable records. Prognosis was considered unfavorable if meningitis sequelae such as quadriplegia, deafness, or epilepsy were present in 3- month follow-up; Based on this definition, 43 (12.7%) had a poor prognosis. No significant relationship was seen between unfavorable prognosis and age or causative pathogen. More had an unfavorable prognosis if treatment was initiated 4 days or later after onset. The percentage with an unfavorable prognosis was 6.4% (4/64) in the group administered combined panipenem/betamipron (PAPM/BP) plus ceftriaxone (CTRX), 10.5% (6/57) administered MEPM plus cefotaxime (CTX), 14.0% (7/50) administered meropenem (MEPM) plus CTRX, and none of the 23 administered CTRX alone. The percentage with an unfavorable prognosis was 26.2% (11/42) in those administered MEPM, significantly higher than that in those administered PAPM/BP plus CTRX, MEPM plus CTX, or CTRX alone (p < 0.05). We concluded that in initial treatment, it would be more desirable to use MEPM combined with another drug than alone.

Trends in empirical chemotherapy of bacterial meningitis in children aged more than 4 months in Japan: a survey from 1997 through 2008.

Bacterial meningitis is a serious problem in pediatric clinics and, therefore, needs urgent and empirical chemotherapy. We investigated 1,116 cases of empirical chemotherapy of patients aged older than 4 months from 1997 through 2008 by sending questionnaires. A single antibiotic treatment was carried out in less than 30% of the cases throughout the years, whereas the combination of two antibiotics had been practiced in more than 70% of the cases. The main antibiotics used were cephalosporins, carbapenems, and ampicillin. Combinatory use of ampicillin and cephalosporin was carried out in 74.7-82.7% of cases in 1997-2000, but sharply declined thereafter to 0-13.8% in 2004-2008. However, the combination of carbapenem and cephalosporin compensated for the decline, increasing from 3.8-6.6% in 1998-1999 to 79.5-89.9% in 2005-2008. The breakdown in the use of cephalosporins, carbapenems, and ampicillin in two-drug combinatory therapy was as follows. (i) Use of cefotaxime was 61.8-75.3% in 1997-2001, but decreased to nearly 50%, equivalent to the level of ceftriaxone use in 2003-2008. (ii) Use of ampicillin dropped from 74.7-92.3% in 1997-2000 to 4.6% in 2008, and this decreased level was compensated for by the use of carbapenems. Overall, combinatory chemotherapy of the third-generation cephalosporins and carbapenems seems to be practical. The discussion in this report includes the difference between Japan and the United States in the prevalence of the causative agents and the use of antibiotics. These studies provide information on trends in the treatment of children's meningitis in Japan and will be useful for the design of future empirical chemotherapy.

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 carbapenem + cephalosporin 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 1 year, 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.

[Childhood bacterial meningitis trends in Japan from 2007 to 2008].

We surveyed pediatrics bacterial meningitis epidemiology from January 2007 to December 2008 in Japan, with the following results: Cases numbered 287-160 male and 127 female-equivalent to 1.54-1.62 of 1,000 pediatric hospitalization per year. Children under 1-year-old accounted for the highest number of cases, which decreased with increasing age. Haemophilus influenzae was the most common cause of infection, followed by Streptococcus pneumoniae, group B streptococcus (GBS), and Escherichia coli. GBS and E. coli were major pathogens in children under 4 months of age, while H. influenzae and S. pneumoniae mainly accounted for those over 4 months of age. Susceptibility tests showed that 51% of H. influenzae isolates and 56.5% of S. pneumoniae isolates in 2008 were drug-resistant. Ampicillin combined with cephem antibiotics effective against GBS, E. coli, and Listeria, were mainly used to initially treat those under 4 months of age. In those over 4 months of age, carbapenem antibiotics are effective against PRSP and cephem antibiotics against H. influenza.

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 MIC(90) 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 MIC(90) 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 the development of drug-resistance in the pediatric field: drug sensitivity of Haemophilus influenzae in Japan.

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.

[Childhood bacterial meningitis trends in Japan from 2005 to 2006].

We surveyed pediatric bacterial meningitis epidemiology from January 2005 to December 2006 in Japan, with the following results. Bacterial meningitis cases numbered 246 -138 boys and 108 girls-, equivalent to 1.7-1.72 children of 1,000 hospitalized in pediatrics per year. The age distribution for infection was highest in those under 1 year of age and decreased with increasing age, Haemophilus influenzae was the most common infection causing the pathogen, followed by Streptococcus pneumoniae, group B streptococcus, and Escherichia coli. The relationship between causative pathogens and age distribution was as follows: group B streptococcus and E. coli were major pathogens in patients under 4 months old and H. influenzae and S. pneumoniae in those over 4 months old. Susceptibility tests at individual facilities showed 59.3% of H. influen- zae isolates and 69.3% of S. pneumoniae isolates in 2004 to be drug-resistant. Ampicillin and cephem antibiotics are effective against GBS, E. coli, and Listeria, so combined of ampicillin and cephem antibiotics are used as first-line antibiotics in many facilities in patients under 4 month old and combined of carbapenem antibiotics effective against PRSP and cephem effective against H. influenzae were the first choice against childhood bacterial meningitis in patients over 4 month old.

[Efficacy and safety of faropenem in pediatric patients with bacterial infectious diseases].

The only oral penem antibiotic, faropenem (FRPM: Farom Dry Syrup for pediatrics), is one of the few antibiotics that exerts potent antibacterial activity against penicillin-resistant Streptococcus pneumoniae (PRSP), and the dosage and administration schedule has been established for children. We studied the efficacy and safety of the drug in 113 pediatric patients with mild-to-moderate bacterial infectious diseases: upper respiratory tract infection (pharyngitis or tonsillitis), acute bronchitis, otitis media and urinary tract infection (UTI). The patients were administered oral FRPM at the dose of 15-30 mg/kg/day three times a day for 3 to 8 days (or 5 to 14 days for group A streptococcal infection). The study drug was found to be clinically effective in 63/70 cases (90.0%) of upper respiratory tract infection, 6/7 cases of acute bronchitis, 16/17 cases (94.1%) of otitis media and 6/6 cases of UTI. FRPM was demonstrated to have very potent antibacterial activity against S. pneumoniae, with a high bacteriological eradication rate. No serious adverse drug reactions were observed. The only side effect was diarrhea in 12.5% of the patients (14/112 cases). There was little difference in the incidence of diarrhea between FRPM and other oral beta-lactam antibiotics. Compliance with FRPM was found to be very good in this study. These findings suggest that FRPM is as useful for the treatment of bacterial infectious diseases in children as oral penicillin and cephem antibiotics.

[Trends in pediatric bacterial meningitis in Japan (2003-2004)].

We surveyed the epidemiology of pediatric bacterial meningitis between January 2003 and December 2004 in Japan, with the following results: Bacterial meningitis cases numbered 233 (132 boys, 98 girls, and 3 unidentified), equivalent to 1.13-1.6 children of 1000 hospitalized in pediatrics per year. The age distribution for the infections was the highest under 1 year of age, decreasing with increasing age. Haemophilus influenzae was the most common pathogen, followed by Streptococcus pneumoniae, group B streptococcus, and Escherichia coli. The relationship between causactive pathogens and age distribution was as follows: group B. streptococcus and E. coli were major pathogens below 4 months of age and H. influenzae and S. pneumoniae were major pathogens above 4 months of age. Susceptibility tests at each facility demonstrated that 65.0% of H. influenzae isolates and 83.0% of S. pneumoniae isolates in 2004 were drug-resistant. Ampicillin and cephem antibiotics are currently effective against GBS, E. coli and Listeria so a combination of ampicillin and cephem antibiotics is used first line at many facilities for patients below 4 months of age. A combination of carbapenem which showed effective against PRSP and cephem which showed effective against H. influenzae is the first choice in childhood bacterial meningitis for patients above 4 months of age.

Prospective surveillance for atypical pathogens in children with community-acquired pneumonia in Japan.

A total of 141 children with community-acquired pneumonia (CAP) were studied prospectively to determine the causative microorganisms. Microbial investigations included examination of postnasal swabs, cultures, polymerase chain reaction (PCR), and serology. The atypical pathogens occurring most frequently were Mycoplasma pneumoniae (58 patients [41.1%]), Chlamydia pneumoniae (4 patients [2.8%]), and concurrent occurrence of both pathogens (1 patient [0.7%]). Patients aged under 4 years showed a relatively lower rate of atypical bacterial etiology compared with those aged 4 years or older. Major bacterial pathogens were detected in 89 patients (atypical pathogens were detected in 28 patients simultaneously), including Streptococcus pneumoniae in 34 patients, Haemophilus influenzae in 60, Moraxella catarrhalis in 48, and multiple pathogens in 42. In patients suspected of having atypical pneumonia, macrolides are recommended.

[The trend of childhood bacterial meningitis in Japan (2000-2002)].

We surveyed the epidemiology of bacterial meningitis in pediatrics between July 2000 and December 2002 in Japan and obtained the following results.: The number of cases of bacterial meningitis was 316 (182 boys and 134 girls), which was equivalent to 1.1-1.7 children out of 1,000 hospitalized those in pediatrics per year. The age-distribution for the infections was the highest under 1 year of age and it decreased as the age increased. Haemophilus influenzae was the most common pathogen causing the infections, followed by Streptococcus pneumoniae, group B streptococcus, and Escherichia coli. Relationship between causing pathogens and age-distribution was as follows: group B streptococcus and E. coli were major pathogens under 4 months of age and H. influenzae and S. pneumoniae were major pathogens over 4 months of age. Susceptibility tests performed at each facility demonstrated that 53.7% of H. influenzae isolates and 67.7% of S. pneumoniae isolates in 2003 were drug-resistant. As ampicillin and cephem antibiotics are effective against GBS, E. coli and Listeria at present, then the combination of ampicillin and cephem antibiotics was used as first line antibiotics in many facilities under 4 month of age and a combination of carbapenem which showed effective against PRSP and cephem which showed effective against H. influenzae is first choice against childhood bacterial meningitis over 4 month of age.

[A successful treatment with micafungin of candidemia due to Candida krusei].

We report a case of candidemia due to Candida krusei after subarachinoid hemorrhage. A 51 year-old male patient consulted us for high fever and increase of CRP 10 days post operation against subarachinoid hemorrhage. There was a temporary decrease in the CRP after administration of ceftazidime (CAZ) but it again when treatment with CAZ was stopped. Because of detected Candida sp. by blood culture, fluconazole was administered i.v. for 5 days, but C. krusei was positive during the treatment. Therefore, fluconazole was replaced with micafungin. The patient became better after the administration with micafungin for 14 days without side effect. Micafungin is effective against candidemia due to C. krusei.

Antagonism between aminoglycosides and beta-lactams in a methicillin-resistant Staphylococcus aureus isolate involves induction of an aminoglycoside-modifying enzyme.

We encountered three clinical isolates of methicillin-resistant Staphylococcus aureus which were susceptible to netilmicin and arbekacin in the absence of beta-lactam antibiotics but which were resistant to them in the presence of beta-lactam antibiotics. One of these strains, KU5801, was used to further investigate the antagonism between aminoglycosides and beta-lactam antibiotics. beta-Lactam antibiotics induced bacterial synthesis of aminoglycoside-6'-N-acetyltransferase and 2"-O-phosphotransferase [AAC(6')-APH(2")] in association with decreased antimicrobial activities of aminoglycosides. A 14.4-kb EcoRI fragment that included the genes that control for beta-lactam-inducible aminoglycoside resistance was cloned from a 31-kb conjugative plasmid present in KU5801. Restriction fragment mapping and PCR analysis suggested that a Tn4001-like element containing a gene encoding AAC(6')-APH(2") was located downstream from a truncated blaZ gene. The DNA sequence between blaR1 and a Tn4001-like element was determined. The Tn4001-IS257 hybrid structure was cointegrated into the blaZ gene, and the typical sequences for the termination of transcription were not found between these regions. We deduced that antagonism of aminoglycosides by beta-lactam antibiotics in isolate KU5801 involved transcription of the aac(6')-Ie-aph(2")-Ia gene under the influence of the system regulating penicillinase production.

Differentiation of beta-lactamase-negative ampicillin-resistant Haemophilus influenzae from other H. influenzae strains by a disc method.

We established breakpoints for differentiating ampicillin (ABPC)-susceptible strains from resistant strains among Haemophilus influenzae isolates according to susceptibility to various beta-lactam antibiotics, using a disc method. Susceptibility testing of isolates for 13 beta-lactam agents was followed by analysis of the resistance genes, using a polymerase chain reaction (PCR) to identify the TEM-1 beta-lactamase gene ( bla) and the ftsI gene encoding penicillin-binding protein (PBP) 3, which affects beta-lactam minimum inhibitory concentrations (MICs). A total of 228 H. influenzae isolates were classified into 114 beta-lactamase-negative, ABPC-susceptible (BLNAS) strains; 29 beta-lactamase-negative, ABPC-resistant (BLNAR) strains; 53 low-BLNAR strains with a low degree of ABPC resistance; 27 TEM-1-producing strains (BLPAR); and 5 strains with ftsI gene mutations in addition to TEM-1 production (BLPACR) according to the PCR results. To identify resistant strains by disc-method susceptibility testing, the zone of inhibition was measured for ABPC (10 microg/disc), cefaclor (30 microg/disc), cefpodoxime (10 microg/disc), and cefdinir (5 microg/disc) discs. Strains were identified as BLNAS without resistant genes when the diameter was > or =27 mm for the ABPC disc and > or =21 mm for the cefaclor disc. Other strains were identified as BLNAR when the diameter was < or =22 mm for the cefpodoxime disc and < or =17 mm for the cefdinir disc. Remaining strains were identified as low-BLNAR. These criteria differentiated resistance types with high accuracy. A discrepancy was noted between genetic results and disc-testing breakpoints for differentiating resistant from susceptible H. influenzae. A disc-testing breakpoint for cefditoren (5 microg/disc) was proposed, with the susceptibility statistically defined as a diameter of > or =24 mm, which corresponds to the breakpoint (1 microg/ml) of the microdilution method recommended by the Japanese Society of Chemotherapy.

[Pharmacokinetic and clinical studies on teicoplanin for sepsis by methicillin-cephem resistant Staphylococcus aureus in the pediatric and neonate field].

Pharmacokinetics, clinical efficacy and safety of teicoplanin (TEIC) were evaluated in pediatric and neonate patients with MRSA sepsis in the dosages approved in overseas. The administrated dose for pediatrics patients was 10 mg/kg once at hour 0, 12 and 24, followed by every 24 hours intervals. In neonates patients, first dose was 16 mg/kg, then 8 mg/kg every 24 hours intervals. 1. Pharmacokinetic results. All 17 patients (9 neonates and 8 pediatrics) who received TEIC were evaluated for pharmacokinetics. Trough concentrations were analyzed in 16 patients (9 neonates and 7 pediatrics) excluding one patient for lack of measurement of drug concentration at day 7. No patient with a concentration exceeding 60 micrograms/mL in peak or trough concentrations were reported. Mean concentrations in trough at day 3, 4 and 7 in neonates were 15.2, 14.7 and 17.8 micrograms/mL, and in pediatrics were 12.5, 12.2 and 13.1 micrograms/mL, respectively. These results were similar to those reported in foreign pediatrics and neonates patients. 2. Efficacy and safety results. Since no patient was excluded, all patients were evaluated for efficacy and safety. Microbiological efficacy as well as clinical cure were secondarily evaluated in 2 patients for whom MRSA was isolated from blood. Clinical efficacy rate was 76.5% (13/17) and number of cases in judgments of excellent, good, fairly improved and no change were 12, 1, 3 and 1 cases respectively. The patients for whom MRSA was isolated from blood were judged as MRSA eradicated case and cured without any additional anti-MRSA drugs. Adverse events were reported in 2 neonates and 3 pediatric patients. Possibly related adverse events to study drug (adverse drug reactions) were: 1 case of respiratory disorder, thrombocythemia, gamma-GTP increased, GOT increased and GPT increased in 3 pediatrics. These results suggest that an application of overseas dose regimen of TEIC for neonate and pediatrics is appropriate in Japan.