Cerebrospinal pharmacokinetic and pharmacodynamic analysis of efficacy of meropenem in paediatric patients with bacterial meningitis.

BACKGROUND: Meropenem is widely used for the treatment of paediatric patients with bacterial meningitis, but the pharmacodynamic (PD) basis for this has not been fully elucidated. OBJECTIVES: A cerebrospinal pharmacokinetic (PK) and PD analysis was performed to identify the optimal dosage regimen for paediatric patients with inflamed central nervous system disease (bacterial men-ingitis). PATIENTS AND METHODS: Paediatric data from three clinical studies were used to build a novel population PK model with a cerebrospinal fluid (CSF) compartment, assuming CSF clearance of 0.021 L/h from a physical-anatomical perspective. The bactericidal target attainment rates in CSF [50%T>MIC(CSF)], after various dosage regimens, were simulated on the basis of reported or observed minimum inhibitory concentration (MIC) distributions and a newly developed population PK model including CSF concentrations. The effects of increased dose and/or prolonged infusion on target attainment were investigated. RESULTS: Clinical data from 154 patients {mean age 30.6 [standard deviation (SD) 34.4] months, mean body weight 12.4 (SD 7.6) kg} were used for the population PK analysis. The flat profile of the CSF concentration-time curve and attainment of 50%T>MIC(CSF) did not change markedly when the duration of infusion was increased, whereas attainment of 50%T>MIC(CSF) was improved by increasing the dose from 20 to 40 mg/kg q8h for penicillin-resistant Streptococcus pneumoniae and Pseudomonas aeruginosa. Thirty-six patients who achieved satisfactory clinical cure showed at least 75.3%T>MIC(CSF). CONCLUSIONS: A high dose of meropenem (40 mg/kg q8h) is necessary to achieve clinical efficacy in paediatric patients with bacterial meningitis.

Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2012: General view of the pathogens' antibacterial susceptibility.

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from the patients in Japan was conducted by Japanese Society of Chemotherapy, Japanese association for infectious diseases and Japanese society for Clinical Microbiology in 2012. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period between January and December in 2012 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical Laboratory Standard Institutes. Susceptibility testing was evaluated in 1236 strains (232 Staphylococcus aureus, 225 Streptococcus pneumoniae, 16 Streptococcus pyogenes, 231 Haemophilus influenzae, 147 Moraxella catarrhalis, 167 Klebsiella pneumoniae and 218 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was 51.3%, and those of penicillin-intermediate S. pneumoniae was 0.4%. Among H. influenzae, 5.6% of them were found to be ß-lactamase-producing ampicillin-resistant strains, and 37.2% to be ß-lactamase-non-producing ampicillin-resistant strains. Extended spectrum ß-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo ß-lactamase were 4.2% and 3.2%, respectively. Continuous national surveillance is important to determine the actual situation of the resistance shown by bacterial respiratory pathogens to antimicrobial agents.

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

BACKGROUND: 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. METHODS: All strains of S. pneumoniae were isolated from clinical specimens collected from pediatric patients. The minimun inhibitory concentration was measured and the strains were classified according to the Clinical Laboratory Standards Institute criteria. The isolation rates of penicillin-intermediate resistant S. pneumoniae (PISP) and penicillin-resistant S. pneumoniae (PRSP) were compared based on seven patient factors. Logistic regression analysis was also performed. RESULTS: The sum of the isolation rates for PISP and PRSP for each period was 64.6%, 67.0%, 56.2%, 76.9% and 49.5%, respectively. Among the patient factors, age category 1 (<3 years, ≥3 years), age category 2 (infant, toddler and preschooler, schoolchild), siblings (absence, presence), and pre-treatment with antimicrobial agents (absence, presence) were associated with significant differences in the isolation rate of PISP + PRSP. An interaction was observed between pre-treatment with antimicrobial agents and schoolchild, and the isolation rate of PISP + PRSP was higher in patients with both pre-treatment with antimicrobial agents and schoolchild. CONCLUSION: Although some changes were observed in the rate of resistance of S. pneumoniae, an increasing trend was not observed. Both pre-treatment with antimicrobial agents and age were associated with resistance, and an interaction was observed between pre-treatment with antimicrobial agents and schoolchild.

Pharmacokinetic evaluation of liposomal amphotericin B (L-AMB) in patients with invasive fungal infection: Population approach in Japanese pediatrics.

The pharmacokinetic characteristics of liposomal amphotericin B (L-AMB; AmBisome(®)) in patients with invasive fungal infection were investigated. A population pharmacokinetic (PK) model in Japanese pediatric patients was developed based on 159 serum amphotericin B (AMPH-B) concentrations obtained in a post-marketing clinical study. The subjects were 39 patients with a mean age of 8.4 years (SD 4.5) and mean body weight of 27.1 kg (SD 14.1). A two-compartment PK model with zero-order input and first-order elimination was fitted to serum AMPH-B concentrations for L-AMB doses of 1.0, 2.5, and 5.0 mg/kg/day. Body weight showed significant correlations with PK parameters, such as clearance (CL) and distribution volume of the central compartment (Vc). The predicted Cmax/dose and AUC0-24/dose in Japanese pediatric patients were similar to those in non-Japanese pediatric patients and Japanese adult patients. Extremely large increases in Ctrough compared with predicted values were observed in some Japanese pediatric patients, but no relationships with demographic characteristics, clinical laboratory test values, or representative adverse drug reaction (decreased potassium) were found. The population PK parameters in this study are useful for simulating PK profiles of L-AMB and will be helpful for PK exposure comparisons among different populations and in investigations of pharmacokinetic-pharmacodynamic characteristics in patients. CHEMICAL COMPOUNDS: Amphotericin B Deoxycholate (PubChem CID:23668620); amphotericin B (PubChem CID:5280965); 3-nitrophenol (PubChem CID:11137); methanol (PubChem CID:887).

Japanese nationwide surveillance in 2011 of antibacterial susceptibility patterns of clinical isolates from complicated urinary tract infection cases.

To investigate antimicrobial susceptibility patterns of various bacterial pathogens isolated from complicated urinary tract infection (UTI) cases, the Japanese Society of Chemotherapy, the Japanese Association of Infectious Disease, and the Japanese Society of Clinical Microbiology conducted the second nationwide surveillance from January to September 2011. With the cooperation of 42 medical institutions throughout Japan, 1036 strains belonging to 8 clinically relevant bacterial species were collected. Among methicillin-resistant Staphylococcus aureus (MRSA) strain, the vancomycin (VCM) MIC for 5.5% (3/55) of the strains was 2 µg/mL. Ampicillin, VCM, and linezolid were relatively active against 209 Enterococcus faecalis strains. The proportion of fluoroquinolone (FQ)-resistant strains was >20%. The MIC90 of FQs against the 382 Escherichia coli strains was 2-64 mg/L and the proportion resistant to FQs was approximately 30%. However, susceptibility of E. coli to sitafloxacin was still high (MIC90 = 2 mg/L). Fifty-eight (15.2%) of 382 E. coli, 6 (4.5%) of 132 Klebsiella pneumoniae, 1 (2.4%) of 41 Klebsiella oxytoca and 4 (6.8%) of 59 Proteus mirabilis strains were suspected of producing extended-spectrum beta-lactamase. Of 93 Pseudomonas aeruginosa strains, the proportions resistant to imipenem, amikacin, and ciprofloxacin were 21.5%, 4.3%, and 20.4%, respectively. Four strains (4.3%) were found to be multidrug-resistant. In complicated UTI cases, all of MRSA and E. faecalis were susceptible to all anti-MRSA agents. Sitafloxacin was active against other FQ-resistant E. coli strains. The isolation of extended-spectrum beta-lactamase-producing and multidrug-resistant strains increased.

Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2010: General view of the pathogens' antibacterial susceptibility.

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from patients in Japan, was conducted by Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases and Japanese Society for Clinical Microbiology in 2010. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period from January and April 2010 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical and Laboratory Standard Institutes using maximum 45 antibacterial agents. Susceptibility testing was evaluable with 954 strains (206 Staphylococcus aureus, 189 Streptococcus pneumoniae, 4 Streptococcus pyogenes, 182 Haemophilus influenzae, 74 Moraxella catarrhalis, 139 Klebsiella pneumoniae and 160 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was as high as 50.5%, and those of penicillin-intermediate and -resistant S. pneumoniae were 1.1% and 0.0%, respectively. Among H. influenzae, 17.6% of them were found to be ß-lactamase-non-producing ampicillin (ABPC)-intermediately resistant, 33.5% to be ß-lactamase-non-producing ABPC-resistant and 11.0% to be ß-lactamase-producing ABPC-resistant strains. Extended spectrum ß-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo ß-lactamase were 2.9% and 0.6%, respectively. Continuous national surveillance of antimicrobial susceptibility of respiratory pathogens is crucial in order to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis.

A very rare case of primary meningococcal arthritis in an adult male.

We report here a very rare case of primary meningococcal arthritis of the knee joint without clinical features associated with meningococcemia, meningitis, or meningococcal complications. The patient suffered from diabetes mellitus and had experienced two episodes of joint trauma. Intravenous infusion of ampicillin/sulbactam for 18 consecutive days was successful.

The second nationwide surveillance of the antimicrobial susceptibility of Neisseria gonorrhoeae from male urethritis in Japan, 2012-2013.

Worldwide, the most important concern in the treatment of sexually transmitted infections is the increase in antimicrobial resistant Neisseria gonorrhoeae strains including resistance to cephalosporins, penicillins, fluoroquinolones or macrolides. To investigate the trends of antimicrobial susceptibility among N. gonorrhoeae strains isolated from male patients with urethritis, a Japanese surveillance committee conducted the second nationwide surveillance study. Urethral discharge was collected from male patients with urethritis at 26 medical facilities from March 2012 to January 2013. Of the 151 specimens, 103 N. gonorrhoeae strains were tested for susceptibility to 20 antimicrobial agents. None of the strains was resistant to ceftriaxone, but the minimum inhibitory concentration (MIC) 90% of ceftriaxone increased to 0.125 µg/ml, and 11 (10.7%) strains were considered less susceptible with an MIC of 0.125 µg/ml. There were 11 strains resistant to cefixime, and the MICs of these strains were 0.5 µg/ml. The distributions of the MICs of fluoroquinolones, such as ciprofloxacin, levofloxacin and tosufloxacin, were bimodal. Sitafloxacin, a fluoroquinolone, showed strong activity against all strains, including strains resistant to other three fluoroquinolones, such as ciprofloxacin, levofloxacin and tosufloxacin. The azithromycin MICs in 2 strains were 1 µg/ml.

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 + ß-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.

Nationwide survey of the development of drug resistance in the pediatric field in 2007, 2010, and 2012: drug sensitivity of Haemophilus influenzae serotype b strain in Japan.

Based on the results of surveillance in the pediatric field conducted in 2007, 2010, and 2012, we examined the frequency of Haemophilus influenzae serotype b (Hib) strains, the susceptibility for Hib strains to various types of antimicrobial agent, and the relations to patients' background factors. Among all of Haemophilus influenzae, the frequency of Hib strains was 3.6% (14/386 strains) in 2007, 4.8% (23/484 strains) in 2010, 1.2% (5/411 strains) in 2012, and decreasing in 2012. Hib strains were isolated in patients with the following infections: nine patients with respiratory tract infections (upper respiratory tract infection, bronchitis, and pneumonia), three patients with sepsis, one patient with meningitis, and one patient with purulent inflammation of a tendon sheath in 2007; 11 patients with respiratory tract infections (upper respiratory tract infection, bronchitis, and pneumonia), four patients with sepsis, and eight patients with meningitis in 2010, demonstrating a relatively high frequency in patients with invasive infections. However, in 2012, Hib strains were isolated in only four patients with respiratory tract infections (upper respiratory tract infection) and one patient with bronchial asthma. Evaluation of background factors with pediatric patients in whom Hib strains were isolated showed that approximately 70% were male; majority was children under three years of age; and higher detection rates were also related to the background of patients who were attendant to daycare center, had siblings, had received no antimicrobial agents within the previous one month before collecting specimens. Throughout the surveillance between 2007 and 2012, antimicrobial agents with all phases' MICs ≤ 1 µg/mL were cefditoren, cefcapene, and cefteram in the oral ß-lactams; tazobactam/piperacillin, ceftriaxone, cefotaxime, and meropenem in the injectable ß-lactams; azithromycin in the macrolide; and levofloxacin in the quinolone. After 2010, MIC ranges were evaluated for tebipenem in the oral ß-lactam (≤ 0.063-0.25 µg/mL), doripenem in the injectable ß-lactam (≤ 0.063-0.5 µg/mL), and tosufloxacin in the quinolone (≤ 0.063 µg/mL). Throughout the surveillance, Hib strains were highly susceptible to the above mentioned antimicrobial agents, and there was no significant change in the susceptibility.

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.

[Effect of new oral antimicrobial agents in outpatient treatment of pneumonia in children].

In November 2004, "Guidelines for the Management of Respiratory Infectious Diseases in Children in Japan" was published ahead of the rest of the world, by Japanese Society of Pediatric Pulmonology/Japanese Society for Pediatric Infectious Diseases, based on the data on causative organisms in the lower respiratory tract. In its 2011 version, classification of the severity of pneumonia was renewed based on the latest information. As a result, many types of pneumonia in children are now classified as mild or moderate. This means that many patients who might have conventionally required hospital treatment can now be managed on an outpatient basis. The reason for realization of the wider range of outpatient treatment is the availability of two new oral antimicrobial agents, tebipenem pivoxil and tosufloxacin tosilate hydrate, for the treatment of infections in children. Analysis of data on medical expenses shows a decreased rate of hospitalization due to pneumonia year by year after launch of these two drugs, suggesting that these drugs have contributed to wider range of outpatient treatment. This manuscript discusses the effect of tebipenem pivoxil and tosufloxacin tosilate hydrate in the treatment of pneumonia.

Antibiotic susceptibility survey of blood-borne MRSA isolates in Japan from 2008 through 2011.

We conducted an antibiotic susceptibility survey of 830 blood-borne methicillin resistant Staphylococcus aureus collected from nationwide hospitals in Japan over a three-year period from January 2008 through May 2011. Antibiotic susceptibility was judged according to the criteria recommended by the Clinical Laboratory Standard Institute. Over 99% of the MRSA showed to be susceptible to teicoplanin, linezolid, sulfamethoxazole/trimethoprim and vancomycin, and over 97% of them were susceptible to daptomycin, arbekacin and rifampin. The majority of the MRSA strains showed resistant to minocycline, meropenem, imipenem, clindamycin, ciprofloxacin, cefoxitin, and oxacillin in the rates of 56.6, 72.9, 73.7, 78.7, 89.0, 99.5, and 99.9%, respectively. Among the MRSA strains, 72 showed reduced susceptibility to vancomycin, including 8 strains (0.96%) of vancomycin-intermediate S. aureus (VISA), 54 (6.51%) of heterogeneous vancomycin-intermediate S. aureus (hVISA), and 55 (5.63%) of ß-lactam antibiotics-induced vancomycin resistant S. aureus (BIVR). Unexpectedly, among the 54 hVISA and 55 BIVR, 45 isolates (83.3% and 81.8%, respectively) showed both hVISA and BIVR phenotypes. A new trend of vancomycin resistance found in this study was that VISA strains were still prevalent among the bacteremic specimens. The high rates of the hVISA/BIVR two-phenotypic vancomycin resistance, and the prevalence of VISA in the bloodborne MRSA call attention in the MRSA epidemiology in Japan.

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.

Influence of prior pandemic A(H1N1)2009 virus infection on invasion of MDCK cells by community-associated methicillin-resistant Staphylococcus aureus.

Secondary bacterial pneumonia due to community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has become a highly publicized cause of death associated with influenza. In this study, we performed the gentamicin-killing assay using Madin-Darby canine kidney (MDCK) cells and MRSA strains to investigate whether prior infection from pandemic A(H1N1)2009 virus (A[H1N1]pdm09) lead to increased invasion of MDCK cells by MRSA. We found that the invasion rate of two MRSA strains (ATCC BAA-1680 [USA 300] and ATCC BAA-1699 [USA 100]) into intact MDCK cell monolayers was 0.29 ± 0.15% and 0.007 ± 0.002%, respectively (p < 0.01, n ≥ 3). In addition, the relative invasion rate of both ATCC BAA-1680 and ATCC BAA-1699 was significantly increased by prior A(H1N1)pdm09 infection of MDCK monolayers from 1 ± 0.28 to 1.38 ± 0.02 and from 1 ± 0.24 to 1.73 ± 0.29, respectively (p < 0.01). These results indicate that ATCC BAA-1680 displays much stronger invasiveness of MDCK cells than ATCC BAA-1699, although invasion of both strains was increased by prior A(H1N1)pdm09 infection. In conclusion, this study provided the first evidence that prior A(H1N1)pdm09 infection facilitates the invasion of MDCK cells by MRSA, presumably due to cellular injury caused by the virus.

[Safety and pharmacokinetics of 400 and 600 mg arbekacin sulfate to healthy male volunteers].

We assessed the safety and pharmacokinetics of arbekacin sulfate (ABK, brand name: Habekacin injection) in single and 7-day multiple administration of ABK 400 and 600 mg as potency to healthy male volunteers. In the single administration of ABK 400 and 600 mg (over 30 min, drip infusion), C(max) values were 41.0 +/- 3.6 microg/mL and 63.0 +/- 9.9 microg/mL, respectively. Serum ABK concentrations at 60 min (C(peak)) after the start of administration were 23.2 +/- 2.9 microg/mL and 38.5 +/- 3.3 microg/mL, respectively, and the mean serum ABK concentrations at 24 hr (C(trough)) after the start of administration were less than 0.4 microg/mL (LOQ: limited of quantitation). C(max), Cpeak and AUC(0-infinity) were increased with doses, and t1/2, CL(tot), CL(r) V(ss) and urinary excretion were comparable at both doses. In the multiple administration of ABK 400 and 600 mg (over 30 min, drip infusion) once a day for 7 days, C(max0, C(peak) and AUC(0-infinity) were comparable from the 1st day through to 7th day and increased with doses. After the administration, the serum ABK concentrations were decreased with time, and the means of C(trough) were 0.4 microg/mL (LOQ) -0.5 microg/mL, which showed ABK has no tendency toward accumulation. In addition, t1/2, CL(tot), CL(r) V(ss) and urinary excretion were constant throughout administration days at either dose, and CL(tot) containing CL(r) was not decreased. There were no notable changes in the functions of the kidney, auditory organs, etc. Based on the above-mentioned results, when ABK 400 or 600 mg was intravenously administered over 30 min once or once a day for 7 days to the healthy male volunteers with normal renal clearance, it is suggested there were no problems in terms of safety, and C(max) were 36.7-54.1 and 44.2-78.5 microg/mL, respectively. In addition, C(trough) was 0.5 microg/mL or lower at either doses and ABK was not accumulated in multiple administration of ABK. ABK was, therefore, expected to have good safety profile and favorable pharmacokinetics.

Immunochromatographic detection of the group B streptococcus antigen from enrichment cultures.

Group B Streptococcus (GBS; Streptococcus agalactiae) is a leading cause of serious neonatal infections. The Centers for Disease Control and Prevention recommends GBS screening for all pregnant women during the 35th to 37th weeks of gestation. Although GBS screening has been performed mainly by the culture-based method, it takes several days to obtain a reliable result. In this study, we developed a rapid immunochromatographic test (ICT) for the detection of GBS-specific surface immunogenic protein in 15 min using an overnight enrichment culture. The ICT was prepared using two anti-Sip monoclonal antibodies. This ICT was able to detect recombinant Sip levels of 0.5 ng/ml, or about 10(6) CFU/ml of GBS cells, in tests with 9 GBS strains of different serotypes. The cross-reactivity test using 26 species of microorganism showed no detectable false-positive result. Reactivity of the ICT with 229 GBS strains showed one false-negative result that was attributable to the production of truncated Sip. Among 260 enrichment cultures of vaginal swabs, 17 produced red to orange pigments in Granada medium, and they were all GBS and Sip positive. Among 219 pigment-negative cultures, 12 were GBS positive and 10 were Sip positive. Two Sip-negative cultures contained GBS cells below the limit of detection by the ICT. Among 207 GBS-negative cultures, only one was Sip positive, which was attributable to GBS cell debris. Thus, the sensitivity and specificity of the ICT appeared to be 93.1% and 99.6%, respectively. The newly developed ICT is readily applicable to clinical use in the detection of GBS.

Nationwide surveillance of the antimicrobial susceptibility of Neisseria gonorrhoeae from male urethritis in Japan.

Neisseria gonorrhoeae is one of the most important pathogens causing sexually transmitted infection, and strains that are resistant to several antimicrobials are increasing. To investigate the trends of antimicrobial susceptibility among N. gonorrhoeae strains isolated from male patients with urethritis, a Japanese surveillance committee conducted the first nationwide surveillance. The urethral discharge was collected from male patients with urethritis at 51 medical facilities from April 2009 to October 2010. Of the 156 specimens, 83 N. gonorrhoeae strains were tested for susceptibility to 18 antimicrobial agents. The prevalence of ß-lactamase-producing strains and chromosomally mediated resistant strains were 7.2 % and 16.5 %, respectively. None of the strains was resistant to ceftriaxone, but the minimum inhibitory concentration (MIC) of ceftriaxone for 7 strains (8.4 %) was 0.125 µg/ml. One strain was resistant to cefixime (MIC 0.5 µg/ml). The MICs of fluoroquinolones, such as ciprofloxacin, levofloxacin, and tosufloxacin, showed a bimodal distribution. The MIC of sitafloxacin was lower than those of the three fluoroquinolones listed here, and it was found that the antimicrobial activity of sitafloxacin was stronger than that of the fluoroquinolones. The MIC of azithromycin in 2 strains was 2 µg/ml, but no high-level resistance to macrolides was detected.

Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2009 and 2010: antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus.

The Japanese surveillance committee conducted the first nationwide surveillance of antimicrobial susceptibility patterns of uropathogens responsible for female acute uncomplicated cystitis at 43 hospitals throughout Japan from April 2009 to November 2010. In this study, the causative bacteria (Escherichia coli and Staphylococcus saprophyticus) and their susceptibility to various antimicrobial agents were investigated by isolation and culturing of bacteria from urine samples. In total, 387 strains were isolated from 461 patients, including E. coli (n = 301, 77.8 %), S. saprophyticus (n = 20, 5.2 %), Klebsiella pneumoniae (n = 13, 3.4 %), and Enterococcus faecalis (n = 11, 2.8 %). S. saprophyticus was significantly more common in premenopausal women (P = 0.00095). The minimum inhibitory concentrations of 19 antibacterial agents used for these strains were determined according to the Clinical and Laboratory Standards Institute manual. At least 87 % of E. coli isolates showed susceptibility to fluoroquinolones and cephalosporins, and 100 % of S. saprophyticus isolates showed susceptibility to fluoroquinolones and aminoglycosides. The proportions of fluoroquinolone-resistant E. coli strains and extended-spectrum ß-lactamase (ESBL)-producing E. coli strains were 13.3 % and 4.7 %, respectively. It is important to confirm the susceptibility of causative bacteria for optimal antimicrobial therapy, and empiric antimicrobial agents should be selected by considering patient characteristics and other factors. However, the number of isolates of fluoroquinolone-resistant or ESBL-producing strains in gram-negative bacilli may be increasing in patients with urinary tract infections (UTIs) in Japan. Therefore, these data present important information for the proper treatment of UTIs and will serve as a useful reference for future surveillance studies.

Nationwide survey of the development of drug resistance in the pediatric field in 2007 and 2010: drug sensitivity of Haemophilus influenzae in Japan (second report).

The Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease conducted national surveillance for Haemophilus influenzae in 2007 (phase 3) and 2010 (phase 4), following the previous surveillance conducted from 2000 to 2001 (phase 1) and in 2004 (phase 2). We examined the antimicrobial susceptibility for H. influenzae derived from clinical specimens of pediatric patients collected nationwide from 27 institutions during phases 3 (386 strains) and 4 (484 strains). The frequency of ß-lactamase-nonproducing ampicillin (ABPC)-resistant (BLNAR) strains, which rapidly increased from 11.4 % in phase 1 to 43.4 % in phase 2, has gradually decreased from 38.3 % in phase 3 to 37.8 % in phase 4. In contrast, On the other hand, the frequency of ß-lactamase-producing strains, which continuously decreased from 8.3 % in phase 1 to 4.4 % in phase 3, has increased to 8.7 % in phase 4. Prevalence of ß-lactamase-producing clavulanic acid/amoxicillin-resistant (BLPACR) strains, especially, has increased from 1.6 % in phase 3 to 4.8 % in phase 4. The oral antimicrobial agents with the lowest MIC90 were levofloxacin in both phases, and tosufloxacin in phase 4 (≤0.063 µg/ml), whereas for intravenous use the corresponding agent was tazobactam/piperacillin in both phases (0.125 µg/ml). There was no increase in the MIC90 of most ß-lactams between phase 3 and phase 4. In relationship to sex, age, presence of siblings, attendance at a daycare center, siblings' attendance at a daycare center, and prior administration of antimicrobial agents within 1 month, the frequency of ß-lactamase-nonproducing ABPC-intermediately resistant (BLNAI) strains + BLNAR strains was high (P = 0.005) in cases with prior administration of antimicrobial agents in phase 3.