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.

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.

Risk factors for recurrent hospital-acquired Clostridium difficile infection in a Japanese university hospital.

BACKGROUND: Clostridium difficile infection (CDI) is a highly prevalent hospital-associated infection. Although most patients respond well to discontinuation of antibiotics, 20%-30% of patients relapse. To initiate early therapeutic measures, the risk factors for recurrent CDI must be identified, although very few Japanese studies have used standard surveillance definitions to identify these risk factors. METHODS: We retrospectively reviewed the medical records of patients with health care facility-onset CDI between August 2011 and September 2013. Patients with diarrhea who were positive for Clostridium difficile (via an enzyme immunoassay) were defined as having CDI. Clinical data (eg, demographics, comorbidities, medication, laboratory results, and clinical outcomes) were evaluated, and multivariate analysis was used to identify risk factors that were associated with recurrent CDI. RESULTS: Seventy-six health care facility-onset CDI cases were identified, with an incidence rate of 0.8 cases per 10,000 patient-days. Fourteen cases (18.4%) were recurrent, with 13 patients having experienced a single recurrent episode and one patient having experienced three recurrent episodes. The 30-day and 90-day mortality rates were 7.9% and 14.5%, respectively. Multivariate analysis revealed that recurrent patients were more likely to have underlying malignant disease (odds ratio: 7.98; 95% confidence interval: 1.22-52.2; P=0.03) and a history of intensive care unit hospitalization (odds ratio: 49.9; 95% confidence interval: 1.01-2,470; P=0.049). CONCLUSION: Intensive care unit hospitalization and malignancy are risk factors for recurrent CDI. Patients with these factors should be carefully monitored for recurrence and provided with appropriate antimicrobial stewardship.

Longterm Safety of Tocilizumab: Results from 3 Years of Followup Postmarketing Surveillance of 5573 Patients with Rheumatoid Arthritis in Japan.

OBJECTIVE: To evaluate the longterm safety of tocilizumab (TCZ) for the treatment of rheumatoid arthritis (RA) in a real-world clinical setting in Japan. METHODS: In this longterm extension of a single-arm, observational postmarketing surveillance study, a total of 5573 patients who initiated intravenous TCZ between April 2008 and July 2009 were observed for 3 years, regardless of its continuation, for incidence of fatal events, serious infections, malignancy, gastrointestinal perforations, and serious cardiac dysfunction. RESULTS: Of the 5573 patients who were enrolled, 4527 patients (81.23%) completed 3 years of followup. There were no increases in the proportions of patients with fatal events, serious infection, malignancy, GI perforation, or serious cardiac dysfunction over 3 years. The all-cause mortality rate during followup was 2.58% (0.95/100 patient-yrs), and the standardized mortality ratio was 1.27 (95% CI, 1.08 to 1.50). Patients who were older with longer disease duration and respiratory comorbidities were more likely to discontinue TCZ treatment following serious infection during the first year. Among patients who completed 3 years of TCZ treatment, serious infection developed at a constant rate during the 3-year treatment period. The proportion of malignancy during followup was 2.24% (0.83/100 patient-yrs), and the standardized incidence ratio was 0.79 (95% CI, 0.66 to 0.95). CONCLUSION: The safety profile of TCZ was consistent over time regarding mortality, serious infections, malignancy, gastrointestinal perforation, and serious cardiac dysfunction. These data confirm the longterm safety of TCZ use in patients with RA in a real-world clinical setting.

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.

Evaluation of an automated rapid diagnostic assay for detection of Gram-negative bacteria and their drug-resistance genes in positive blood cultures.

We evaluated the performance of the Verigene Gram-Negative Blood Culture Nucleic Acid Test (BC-GN; Nanosphere, Northbrook, IL, USA), an automated multiplex assay for rapid identification of positive blood cultures caused by 9 Gram-negative bacteria (GNB) and for detection of 9 genes associated with ß-lactam resistance. The BC-GN assay can be performed directly from positive blood cultures with 5 minutes of hands-on and 2 hours of run time per sample. A total of 397 GNB positive blood cultures were analyzed using the BC-GN assay. Of the 397 samples, 295 were simulated samples prepared by inoculating GNB into blood culture bottles, and the remaining were clinical samples from 102 patients with positive blood cultures. Aliquots of the positive blood cultures were tested by the BC-GN assay. The results of bacterial identification between the BC-GN assay and standard laboratory methods were as follows: Acinetobacter spp. (39 isolates for the BC-GN assay/39 for the standard methods), Citrobacter spp. (7/7), Escherichia coli (87/87), Klebsiella oxytoca (13/13), and Proteus spp. (11/11); Enterobacter spp. (29/30); Klebsiella pneumoniae (62/72); Pseudomonas aeruginosa (124/125); and Serratia marcescens (18/21); respectively. From the 102 clinical samples, 104 bacterial species were identified with the BC-GN assay, whereas 110 were identified with the standard methods. The BC-GN assay also detected all ß-lactam resistance genes tested (233 genes), including 54 bla(CTX-M), 119 bla(IMP), 8 bla(KPC), 16 bla(NDM), 24 bla(OXA-23), 1 bla(OXA-24/40), 1 bla(OXA-48), 4 bla(OXA-58), and 6 blaVIM. The data shows that the BC-GN assay provides rapid detection of GNB and ß-lactam resistance genes in positive blood cultures and has the potential to contributing to optimal patient management by earlier detection of major antimicrobial resistance genes.

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.

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.

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 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.

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.

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.

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.