Pharmacokinetic study of lascufloxacin in non-elderly healthy men and elderly men.

We conducted this phase I clinical study to examine the pharmacokinetic profiles and safety of lascufloxacin (LSFX), a novel quinolone antibacterial agent, in non-elderly Japanese healthy men and the effects of aging on LSFX pharmacokinetics in elderly Japanese healthy men. 1. After single-dose oral administration of LSFX 100-800 mg (capsules) to six healthy adults in fasting state, the Cmax and AUClast roughly increased in proportion to the doses. 2. After multiple-dose oral administration of LSFX 75 mg (tablets) once daily for 7 days to six healthy adults, plasma LSFX reached the steady state by Day 7. The cumulative factor of LSFX on Day 7 to Day 1 was 1.65 for the Cmax and 1.96 for the AUCtau. 3. Regarding pharmacokinetic parameters of plasma LSFX after single-dose administration of LSFX 75 mg tablets (final product) to 24 healthy adults in fed state, the Cmax was somewhat higher, 1.28 times more than that in fasting state, whereas no changes were found in the AUClast. We therefore proposed that food effects of LSFX on absorption were negligible. 4. No clinically significant safety problems of LSFX were found in a series of studies involving healthy adults conducted this time. 5. After single-dose oral administration of LSFX 200 mg (capsules) to six elderly people in fasting state, its pharmacokinetic parameters were similar to those in non-elderly people, with no significant safety concerns. Therefore, adjustment of dosage and administration was considered to be unnecessary for LSFX administration to elderly individuals.

Nationwide surveillance of 6 otorhinolaryngological infectious diseases and antimicrobial susceptibility pattern in the isolated pathogens in Japan.

The Japanese Three Academic Societies Joint Antimicrobial Susceptibility Surveillance Committee has conducted a nationwide surveillance on antimicrobial susceptibility patterns and rates of isolation in 6 otolaryngological diseases. The surveillance program was conducted in the otorhinolaryngological departments of 29 universities, and their 26 affiliated hospitals. Patients suffering from acute otitis media, chronic otitis media, acute nasal sinusitis, chronic nasal sinusitis, acute tonsillitis, and peritonsillar abscess between January 2011 and June 2012 were investigated. The collected swab or incision samples were cultivated for microbial identification, and the drug susceptibility of detected bacteria was measured at the Kitasato University Research Center for Infections and Antimicrobials. The surveillance focused on three gram-positive bacteria (Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus), three gram-negative bacteria (Haemophilus influenzae, Moraxella Catarrhalis, and Pseudomonas aeruginosa), and three anaerobic bacteria (Peptostreptococcus spp., Prevotella spp., and Fusobacterium spp.). Bacterial susceptibility to 39 antimicrobial drugs was investigated. We compared bacterial isolation ratio of each disease in this surveillance from those of past 4 times surveillance which we performed formerly, and we also compared percentage of main drug resistant strains from those of past 4 times surveillance. The age composition between this time and former surveillances was not statistically significant by student-t test. We were unable to completely resolve the rise in resistant bacteria, such as methicillin-resistant S. aureus, penicillin-resistant S. pneumoniae, penicillin-intermediate resistant S. pneumoniae, beta-lactamase non-producing ampicillin-resistant H. influenzae, beta-lactamase producing ampicillin-resistant H. influenzae, and beta-lactamase producing amoxicillin clavulanic acid-resistant H. influenzae. We suggest promoting the proper usage of antimicrobial drugs in order to avoid the spread of these bacteria.

Cefazolin therapy for methicillin-susceptible Staphylococcus aureus bacteremia in Japan.

This is a retrospective cohort study of patients who were treated with cefazolin for methicillin-susceptible Staphylococcus aureus bacteremia, at Tokyo Women's Medical University Hospital between January 2006 and December 2010. During the study period, 84/140 (60%) patients received cefazolin (mean age, 54 years; range, 0-94 years, male patients 64%). Of these, 60/84 (71%) cases were hospital acquired infections, 55/84 (65%) had heart disease, and 19/84 (23%) had moderate to severe heart failure (New York Heart Association class III/IV). The treatment failure rate at 12 weeks was 35% (n = 29). All-cause mortality were 15% (n = 13) after 12 weeks and 21% (n = 18) after a year. Secondary endocarditis and neurological events were observed in 10% (n = 8) and 2% (n = 2). Moderate to severe heart failure and retained intravascular devices were associated with treatment failure at 12 weeks by multivariate analysis (P < 0.01, P = 0.018). Our results suggest that hospital-acquired methicillin-susceptible S. aureus bacteremia can cause severe complications in patients with moderate to severe heart failure who retain their intravascular devices. Both effective antimicrobial therapy and removal of infected foci are essential for S. aureus bacteremia treatments.

Population pharmacokinetics and pharmacodynamics of sitafloxacin in patients with community-acquired respiratory tract infections.

An optimal dosage regimen of sitafloxacin was considered based on a pharmacokinetics and pharmacodynamics (PK-PD) analysis in patients with community-acquired respiratory tract infections (RTI). A population pharmacokinetic analysis of sitafloxacin was conducted using clinical data of five clinical pharmacology studies and one clinical PK-PD study in patients with RTIs. The pharmacokinetic parameters in individual patients were estimated by the Bayesian method to examine any correlation between pharmacokinetics and bacteriological efficacy. Efficacy data were obtained from the clinical PK-PD study, in which 50 or 100 mg sitafloxacin was administered twice daily for 7 days. In addition, an efficacy was simulated for a hypothetical dose regimen of 100 mg once daily. The fAUC(0-24h)/MIC and the fC max/MIC of sitafloxacin at a dose of 50 mg twice daily were 117.5 ± 78.0 and 7.3 ± 4.7 (mean ± SD), respectively. As a result of the univariate logistic regression analysis, the larger the value of fAUC(0-24h)/MIC or fC max/MIC becomes, the higher the bacteriological efficacies. The eradication rates for fAUC(0-24h)/MIC ≥ 30 and for fC max/MIC ≥ 2 were 96.4% and 96.3%, respectively. The PK-PD target values of sitafloxacin for the treatment of mild to moderate RTIs were considered to be fAUC(0-24h)/MIC ≥ 30 and fC max/MIC ≥ 2. The PK-PD parameters at the regimen of 50 or 100 mg twice daily in patients with RTIs reached the target values. Furthermore, a 100 mg once-daily regimen was expected to show similar efficacy based on the PK-PD simulations.

Clinical efficacy and safety of arbekacin sulfate in patients with MRSA sepsis or pneumonia: a multi-institutional study.

Arbekacin (ABK) is an aminoglycoside and widely used in Japan for treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). Although, ABK has concentration-dependent antibacterial activity, the peak serum concentration (C (peak)) of ABK has not yet been fully investigated as an indicator of the efficacy of ABK. The present study was conducted in patients admitted to hospitals affiliated with the ABK Dose Finding Study Group, between October 2008 and June 2011, who had pneumonia or sepsis, the cause of which was identified or suspected to be MRSA. The initial target C (peak) was set at 15-20 µg/mL and therapeutic drug monitoring was conducted. Then the relationship between serum concentration and efficacy/safety of ABK was prospectively examined to obtain sufficient clinical efficacy. In total, 89 patients from 11 clinical sites in Japan were enrolled and 29 of these patients were subjected to efficacy analysis. The mean initial dose and C (peak) were 306.9 mg/day and 16.2 µg/mL, respectively. The efficacy rate was 95 % (19/20 patients) at 5-6 mg/kg or higher, 87.5 % (7/8) for sepsis and 90.5 % (19/21) for pneumonia, and the overall efficacy rate was 89.7 % (26/29). There was no increase in the incidence of adverse events. In conclusion, we recommend the initial dose of ABK at 5-6 mg/kg or higher and the dosage regimen should be adjusted to achieve C (peak) at 10-15 µg/mL or higher in the treatment of patients with pneumonia or sepsis caused by MRSA. This strategy would surely achieve low incidence of adverse events while obtaining high clinical efficacy.

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.

Acquired hemophilia A in a patient with essential thrombocythemia.

A 69-year-old woman with essential thrombocythemia (ET) developed giant ecchymosis, and she was admitted to hospital. Marked anemia (Hb 8.1 g/dl) accompanied by a prolonged activated partial thromboplastin time (89.6 s) was observed, and she received red blood cells (RBC) and fresh frozen plasma (FFP). On day 2 after admission, consciousness disturbance suddenly occurred, whereas computed tomography of the brain showed no evidence of bleeding. As the ecchymosis progressed, she developed shock. Although RBC and FFP transfusions were administered, she developed multi-organ failure and died 48 h after admission. Low factor VIII activity (<1%) accompanied by factor VIII inhibitor (17 Bethesda units) was found after her death. An autopsy revealed cerebral infarction without cerebral herniation. To date, acquired hemophilia A accompanying ET has been described in only one other patient. Although acquired factor VIII inhibitor is a rare disease, it should be tested for in ET patients with marked hemorrhagic tendency.

Analysis of clinical features of non-HIV Pneumocystis jirovecii pneumonia.

Pneumocystis jirovecii pneumonia (PCP) is classified as PCP with human immunodeficiency virus (HIV) and non-HIV PCP, and the two forms differ in progression and prognosis. Although early treatment is necessary, the diagnosis of non-HIV PCP is often difficult because of the underlying diseases. However, the outcome with treatment delay remains unclear because there are no concrete data indicating a worsened clinical situation or increased complications related to delayed therapy initiation. We retrospectively examined patients with non-HIV PCP admitted to Tokyo Women's Medical University Hospital from November 2008 to October 2010. The relationship between intubation with mechanical ventilation (within 1 week after starting treatment) and treatment delay was investigated. Treatment delay was defined as the period, in days, from onset to therapy initiation. In total, 24 confirmed non-HIV PCP cases were included. Median treatment delay was 7 ± 4.83 days (1-20 days). Twelve of 24 cases (50 %) were intubated, and 11 (45.8 %) died of their underlying diseases within 90 days. Treatment delay was more than 7 days in the intubation group, but was within 7 days in 9 of 12 nonintubation cases. The difference in treatment delay was significant (p = 0.0071) between the intubation and nonintubation groups, but there were no significant differences in survival rate at 90 days or other findings. We conclude that starting treatment within 7 days after onset is important because intubation and mechanical ventilation may be avoided in many cases.

Nationwide surveillance of antimicrobial susceptibility patterns of pathogens isolated from surgical site infections (SSI) in Japan.

To investigate the trends of antimicrobial resistance in pathogens isolated from surgical site infections (SSI), a Japanese surveillance committee conducted the first nationwide survey. Seven main organisms were collected from SSI at 27 medical centers in 2010 and were shipped to a central laboratory for antimicrobial susceptibility testing. A total of 702 isolates from 586 patients with SSI were included. Staphylococcus aureus (20.4 %) and Enterococcus faecalis (19.5 %) were the most common isolates, followed by Pseudomonas aeruginosa (15.4 %) and Bacteroides fragilis group (15.4 %). Methicillin-resistant S. aureus among S. aureus was 72.0 %. Vancomycin MIC 2 µg/ml strains accounted for 9.7 %. In Escherichia coli, 11 of 95 strains produced extended-spectrum ß-lactamase (Klebsiella pneumoniae, 0/53 strains). Of E. coli strains, 8.4 % were resistant to ceftazidime (CAZ) and 26.3 % to ciprofloxacin (CPFX). No P. aeruginosa strains produced metallo-ß-lactamase. In P. aeruginosa, the resistance rates were 7.4 % to tazobactam/piperacillin (TAZ/PIPC), 10.2 % to imipenem (IPM), 2.8 % to meropenem, cefepime, and CPFX, and 0 % to gentamicin. In the B. fragilis group, the rates were 28.6 % to clindamycin, 5.7 % to cefmetazole, 2.9 % to TAZ/PIPC and IPM, and 0 % to metronidazole (Bacteroides thetaiotaomicron; 59.1, 36.4, 0, 0, 0 %). MIC90 of P. aeruginosa isolated 15 days or later after surgery rose in TAZ/PIPC, CAZ, IPM, and CPFX. In patients with American Society of Anesthesiologists (ASA) score ≥3, the resistance rates of P. aeruginosa to TAZ/PIPC and CAZ were higher than in patients with ASA ≤2. The data obtained in this study revealed the trend of the spread of resistance among common species that cause SSI. Timing of isolation from surgery and the patient's physical status affected the selection of resistant organisms.

Development of interpretive criteria for tebipenem disk diffusion susceptibility testing with Staphylococcus spp. and Haemophilus influenzae.

Disk diffusion susceptibility interpretive criteria for tebipenem against Staphylococcus spp. and Haemophilus influenzae were developed using the Clinical and Laboratory Standards Institute (CLSI) guidelines. Tebipenem was tested by disk diffusion and broth microdilution methods against 119 clinical isolates of Staphylococcus spp. and 102 clinical isolates of H. influenzae. The zone diameters of 5-, 10-, and 30-µg disks were compared with broth microdilution minimum inhibitory concentration (MIC) results by scattergram and regression analysis. When the MIC breakpoint of 1 µg/ml was applied to the scattergrams, the 10-µg disk showed good correlation between the zone diameters and the MIC values. The corresponding disk diffusion zone diameter breakpoints with the 10-µg disk for Staphylococcus spp. were ≧22 mm (MIC ≦1 µg/ml) for susceptible, 20-21 mm (MIC = 2 µg/ml) for intermediate, and ≦19 mm (MIC ≧4 µg/ml) for resistant. We also proposed the breakpoint zone diameter of H. influenzae: ≧22 mm (MIC ≦1 µg/ml) for susceptible. These criteria demonstrated that the categorical agreements between disk diffusion and broth microdilution methods for Staphylococcus spp. and H. influenzae were 95.0% and 99.0%, respectively. The discrepancy rates of these criteria were acceptable to the CLSI guidelines.

The nationwide study of bacterial pathogens associated with urinary tract infections conducted by the Japanese Society of Chemotherapy.

This study was conducted by the Japanese Society of Chemotherapy and is the first nationwide study on bacterial pathogens isolated from patients with urinary tract infections at 28 hospitals throughout Japan between January 2008 and June 2008. A total of 688 bacterial strains were isolated from adult patients with urinary tract infections. The strains investigated in this study are as follows: Enterococcus faecalis (n = 140), Escherichia coli (n = 255), Klebsiella pneumoniae (n = 93), Proteus mirabilis (n = 42), Serratia marcescens (n = 44), and Pseudomonas aeruginosa (n = 114). The minimum inhibitory concentrations of 39 antibacterial agents used for these strains were determined according to the Clinical and Laboratory Standards Institute (CLSI) manual. All Enterococcus faecalis strains were susceptible to ampicillin and vancomycin. Although a majority of the E. faecalis strains were susceptible to linezolid, 11 strains (7.8%) were found to be intermediately resistant. The proportions of fluoroquinolone-resistant Enterococcus faecalis, Escherichia coli, Proteus mirabilis, and S. marcescens strains were 35.7%, 29.3%, 18.3%, and 15.2%, respectively. The proportions of E. coli, P. mirabilis, K. pneumoniae, and S. marcescens strains producing extended-spectrum ß-lactamase were 5.1%, 11.9%, 0%, and 0%, respectively. The proportions of Pseudomonas aeruginosa strains resistant to carbapenems, aminoglycosides, and fluoroquinolones were 9.2%, 4.4%, and 34.8%, respectively, and among them, 2 strains (1.8%) were found to be multidrug resistant. These data present important information for the proper treatment of urinary tract infections and will serve as a useful reference for periodic surveillance studies in the future.

Disseminated cryptococcosis in a non-Hodgkin's lymphoma patient with late-onset neutropenia following rituximab-CHOP chemotherapy: a case report and literature review.

Rituximab-related late-onset neutropenia (R-LON) is an adverse event associated with rituximab. A 65-year-old woman presented with diffuse large B-cell lymphoma of the kidney without bone marrow involvement. She was treated with 4 cycles of CHOP chemotherapy consisting of doxorubicin, cyclophosphamide, vincristine, and prednisolone at 4-week intervals. Rituximab was also administrated of the second, third, fourth CHOP cycles. She developed a high fever of 38°C, nausea, and severe neutropenia following the four cycles of R-CHOP chemotherapy. Her leukocyte count was 160/µl without neutrophils. Initially, a blood and pleural fluid and cerebrospinal fluid cultures were positive for Cryptococcus neoformans. Once she became asymptomatic following treatment with fluconazole and neutropenia was recovered with lenograstim, she had neck stiffness and admitted soon. Cerebro-spinal fluid (CSF) culture was positive for Cryptococcus neoformans. Treatment with amphotericin B(AMPH-B) and flucytosine(5-FC) was initiated as diagnosis of cryptococcus meningitis. Lenograstim was administrated for 9 months, and amount of dose was 9,750 µg. Cryptococcosis with malignant lymphoma is rare disease, and previously 17 cases were reported. Of note, mortality of disseminated cryptococcosis with malignant lymphoma is 54%. The more and more rituximab is widely used; the cases of severe infection in R-LON may increase.

Ceftriaxone plus gentamicin or ceftriaxone alone for streptococcal endocarditis in Japanese patients as alternative first-line therapies.

This study included 31 patients who had definite or possible infectious endocarditis as defined by the modified Duke's criteria Of these patients, 27 were treated with ceftriaxone plus gentamycin combination therapy and four with ceftriaxone monotherapy. Of these 31 cases, 29 had infections with Streptococcus species, and showed good responses to penicillin G and cefotaxime. Excluding one patient who died because of the underlying disease, all patients achieved clinical cure after treatment with either of the two regimens, showing no recurrence during a follow-up period of 6 months after completion of drug treatment. Although valve replacement was performed in 10 patients during the follow-up period, there were no recurrences in any of these patients 6 months postoperatively. Ceftriaxone allows a simple regimen of once-daily administration. Although indications are limited, ceftriaxone therapy is feasible on an outpatient basis, offering favorable medical economics. Consistent with previous reports, the therapeutic effect of ceftriaxone was equivalent to that of penicillin G in this study, showing this agent to be an alternative first-line drug for infectious endocarditis.

[Listeriosis in non-Hodgkin's lymphoma following outpatient R-CHOP therapy].

Non-Hodgkin's lymphoma, a hematolymphoid malignancy, puts subjects at risk for complete infection. A 65-year-old man with non-Hodgkin's lymphoma Stage IV had undergone 5 R-CHOP courses in May 2008. Six days later, he was hospitalized for a high fever for which he was initially administered cefepime. When blood culture was positive for Listeria monocytogenes, he was administered ampicillin. His medical interview indicated that he had gone hunting and dressed wild animal meat at his mountain retreat, where he was exposed to wild animals and their excreta following R-CHOP course 5. CSF was not checked because his general condition was good. On hospital day 2, his fever dropped, and he was discharged following two weeks of ampicillin administration. Listeriosis cases reported in Japan number far fewer than in the United States, France or Germany. From January 1983 to February 2009, 153 cases were reported in Japan, 12 of whom were cancer patients. Despite the high incidence of meningitis with listeriosis, 7 of the 12 were not examined for CSF--an examination necessary in listeriosis, however well the subject appears.

[Clinical efficacy, safety and PK-PD analysis of tebipenem pivoxil in a phase II clinical trial in otolaryngological infections].

UNLABELLED: We conducted a double-blind intergroup comparative study investigating the efficacy, safety and PK-PD analysis of the new oral carbapenem antibacterial drug tebipenem pivoxil (TBPM-PI) for the treatment of otolaryngological infections in adults to establish the recommended clinical dosage. The primary endpoint was the clinical effect of a 7-day oral administration of TBPM-PI to subjects with confirmed cases of infection by any of the 5 major bacterial species causative for otolaryngological infections (Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, and Haemophilus influenzae) assigned to three groups set according to the TBPM-PI dosage, namely, a 450 mg group (150 mg t.i.d), a 500 mg group (250 mg b.i.d), and a 900 mg group (300 mg t.i.d). 1. Clinical efficacy: At the end of administration or at discontinuation, the efficacy rate for the 112 subjects in the efficacy analysis set was 72.1% (31/43 subjects) in the 450 mg group, 88.6% (31/35 subjects) in the 500 mg group, and 85.3% (29/34 subjects) in the 900 mg group. Both the 500 mg and 900 mg groups showed a high efficacy rate of over 80%. 2. Bacteriological efficacy: The disappearance rate of the pre-administration causative bacteria (5 major bacterial species) at the end of administration (at discontinuation), it was 92.2% (47/51 strains) in the 450 mg group, 94.7% (36/38 strains) in the 500 mg group, and 91.7% (33/36 strains) in the 900 mg group. All the groups showed a high disappearance rate, with no large differences among them. All strains of S. pneumoniae, including PRSP, as well as those of S. pyogenes and M. catarrhalis disappeared. The overall disappearance rate of H. influenzae was 78.6%, namely, 76.9% in the 450 mg group, 100% in the 500 mg group, and 66.7% in the 900 mg group, showing differences among the groups. 3. PK-PD: The PK-PD analysis was executed in 124 strains isolated from 111 subjects in which the plasma TBPM concentration and the MIC of causative organism were measured. The target value of the PK-PD parameter was examined from the relation between PK-PD parameter and bacteriological efficacy. The presumed target value of AUCf/MIC was 10-20, Cmaxf/MIC was 4. On the other hand, a clear relation was not found between T>MIC and the bacteriological efficacy. 4. SAFETY: The incidence of adverse reactions related to symptoms and signs was 28.8% (21/73 subjects) in the 450 mg group, 35.8% (24/67 subjects) in the 500mg group, and 30.6% (22/72 subjects) in the 900 mg group. The incidence of abnormal changes in laboratory test values was 8.2% (6/73 subjects) in the 450 mg group, 9.2% (6/65 subjects) in the 500 mg group, and 9.9% (7/71 subjects) in the 900 mg group. There were no differences in either of these categories among the groups, and the incidence was considered not to be correlated with dose. Based on the above, we considered that TBPM-PI at doses of 250 mg b.i.d (500 mg/day) promises high clinical usefulness for the treatment of otolaryngological infections in adults.

[Pharmacokinetics analysis of tebipenem pivoxil in a phase II clinical trial in otolaryngological infections].

In a phase IIb clinical study (dose-finding test, 450 mg dosing group: 150 mg t.i.d., 500 mg dosing group: 250 mg b.i.d., 900 mg dosing group: 300 mg t.i.d.) of tebipenem pivoxil (TBPM-PI) for treatment of otolaryngological infections in adults, TBPM concentrations in the patient plasma were quantified. The primary pharmacokinetic parameters such as ka, kel, Vd/F and Tlag were estimated by the Bayesian method and then the secondary pharmacokinetic parameters such as tmax, Cmax, t1/2 and AUC were calculated. As for the patients whose primary parameters were not properly estimated by the Bayesian method, the secondary parameters were calculated by the trapezoidal method. The primary pharmacokinetic parameters obtained by the Bayesian method in 450 mg dosing group (150 mg t.i.d.), 500 mg dosing group (250 mg b.i.d.), and 900 mg dosing group (300 mg t.i.d.) were 5.64 +/- 2.76, 5.11 +/- 3.06 and 2.51 +/- 1.13 hr(-1) for ka, 1.75 +/- 0.25, 2.03 +/- 0.10 and 1.34 +/- 0.27 hr(-1) for kel, 17.62 +/- 5.09, 15.83 +/- 6.14 and 19.34 +/- 8.80 L for Vd/F, and 0.48 +/- 0.11, 0.38 +/- 0.03 and 0.39 +/- 0.26 hr for Tlag, respectively. The secondary parameters obtained by the Bayesian method and the trapezoidal method were 0.85 +/- 0.29, 0.81 +/- 0.33 and 1.18 +/- 1.53 hr for tmax, 5.08 +/- 2.05, 7.92 +/- 4.02 and 8.69 +/- 4.01 microg/ml for Cmax, 0.40 +/- 0.06, 0.34 +/- 0.01 and 0.54 +/- 0.10 hr for t1/2, 5.22 +/- 1.90, 7.93 +/- 4.04 and 13.62 +/- 6.29 microg x hr/ml for AUC after each dosing (AUC(0-8h) or AUC(0-12h)) and 15.65 +/- 5.70, 15.85 +/- 8.08 and 40.87+/- 18.87 microg x hr/ml for AUC(0-24h), respectively. As shown in the above, Cmax and AUC after each dosing were increased with a rise in the dose level, and AUC(0-24h) was increased with a rise in the total dose level per day. Regardless of the dosage, tmax was about 0.8-1.2 hr and t1/2 was about 0.3-0.5 hr, showing almost constant values. Changes in the regimen and dosage did not influence the pharmacokinetic properties of TBPM-PI. Pharmacokinetics of TBPM-PI in adult patients with otolaryngological infection were similar to those in healthy subjects.

Prevalence of toxic shock syndrome toxin 1 (TSST-1)-producing strains of Staphylococcus aureus and antibody to TSST-1 among healthy Japanese women.

Many cases of neonatal toxic shock syndrome (TSS)-like exanthematous disease but few cases of menstrual TSS (mTSS) have been reported in Japan. We determined the prevalence of mucosal colonization with Staphylococcus aureus and of positive antibodies to TSS toxin 1 (TSST-1) among 209 healthy Japanese women in Tokyo. S. aureus isolates from mucosal sites were characterized with respect to TSST-1 production and resistance genotype. Antibody titers were determined for test subjects and for 133 Japanese and 137 Caucasian control women living in the United States. S. aureus was isolated from at least one site in 108 of 209 women (52%) in Tokyo. Of the 159 S. aureus isolates recovered, 14 (9%) were TSST-1 positive (12 unique strains). Twelve of 209 women (6%) were colonized with a TSST-1-producing strain; two (<1%) had vaginal colonization. Only 2 of 12 unique toxigenic strains (14%) were methicillin resistant. Of the 12 TSST-1-positive strains isolated, 6 (50%) were pulsed-field gel electrophoresis type USA200, multilocus sequence type clonal complex 30. Fewer Japanese women in Tokyo (47%) than Caucasian and Japanese women in the United States (89% and 75%, respectively) had TSST-1 antibodies. The prevalences of colonization with TSST-1-producing S. aureus were comparable in Japan and the United States, despite low seropositivity to TSST-1 in Japan. Environmental factors appear to be important in promoting the development of anti-TSST-1 antibodies, as there was a significant difference in titers between Japanese women living in Tokyo and those living in the United States. Most colonizing TSST-1-producing S. aureus strains in Japan were genotypically similar to mTSS strains found in the United States.

Multicenter Study of the Clinical Presentation of Staphylococcus lugdunensis Bacteremia in Japan.

Staphylococcus lugdunensis (SL) is a bacterium with a highly pathogenicity than most other coagulase-negative Staphylococcus spp. (CoNS). In Japan, data on this pathogen are sparse, and the current prevalence of SL bacteremia is unknown. Therefore, we investigated the prevalence of SL in blood culture specimens in a prospective multicenter study across 5 facilities. A total of 3,284 patients had positive blood cultures, and 2,478 patients had bacteremia. Among the patients with bacteremia, 7 patients (0.28%) had SL bacteremia. A total of 281 patients had CoNS bacteremia, with SL accounting for 2.49% of these cases. Of the 7 patients with SL bacteremia, 1 patient (14.3%) had infective endocarditis, and 1 patient (14.3%) died within 30 days. In this study, SL resulted in the development of bacteremia in select patients. Clinicians in Japan should be aware of the prevalence of SL and the complications of SL bacteremia.