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.