Clostridium butyricum-induced ω-3 fatty acid 18-HEPE elicits anti-influenza virus pneumonia effects through interferon-λ upregulation.

The precise mechanism by which butyrate-producing bacteria in the gut contribute to resistance to respiratory viral infections remains to be elucidated. Here, we describe a gut-lung axis mechanism and report that orally administered Clostridium butyricum (CB) enhances influenza virus infection resistance through upregulation of interferon (IFN)-λ in lung epithelial cells. Gut microbiome-induced ω-3 fatty acid 18-hydroxy eicosapentaenoic acid (18-HEPE) promotes IFN-λ production through the G protein-coupled receptor (GPR)120 and IFN regulatory factor (IRF)-1/-7 activations. CB promotes 18-HEPE production in the gut and enhances ω-3 fatty acid sensitivity in the lungs by promoting GPR120 expression. This study finds a gut-lung axis mechanism and provides insights into the treatments and prophylaxis for viral respiratory infections.

In vivo study assessed meropenem and amikacin combination therapy against carbapenem-resistant and carbapenemase-producing Enterobacteriaceae strains.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE), especially for carbapenemase-producing Enterobacteriaceae (CPE), is an emerging cause that pose a significant threat to public health. However, efficient therapy has not been established. We assessed the antimicrobial efficacy of meropenem (MEPM) and amikacin (AMK) combination therapy. MATERIAL AND METHODS: Total eight isolates of Escherichia coli or Klebsiella pneumoniae, including CRE and/or CPE have carbapenemase genes were used. The relationship between phenotype and in vivo efficacy was assessed in neutropenic murine thigh infection model. Efficacy was determined using the change in bacterial density and survival rate. RESULTS: The combination therapy showed enhanced antimicrobial activities against CRE+/CPE+ and CRE+/CPE-K. pneumoniae isolates than MEPM monotherapy (0.63 ± 0.04 vs. 2.56 ± 0.24 ⊿log10 cfu/mL, p < 0.05; -1.05 ± 0.15 vs. -0.48 ± 0.30 ⊿log10 cfu/mL, p < 0.05). Likewise, the combination therapy showed enhanced antimicrobial activities against CRE+/CPE+ and CRE+/CPE-E. coli isolates than MEPM monotherapy (0.90 ± 0.68 vs. 1.86 ± 0.23 ⊿log10 cfu/mL, p < 0.05; -1.81 ± 0.06 vs. -0.88 ± 0.23 ⊿log10 cfu/mL, p < 0.05). Also, combination therapy group showed similar to higher survival rates in CRE + E. coli infection mice, compared to MEPM monotherapy group. CONCLUSION: Our results are the first supportive data to threat CRE infections with combination therapy of MEPM and AMK with in vivo model. The current results verify the promising utility of the combination therapy with MEPM and AMK against CRE isolates with a wide range of MEPM MICs.

Effect of High Blood Glucose Level on the Antimicrobial Activity of Daptomycin against Staphylococcus aureus in Streptozotocin-Induced Diabetic Mice.

Daptomycin is active against Staphylococcus aureus including methicillin-resistant S. aureus (MRSA), demonstrating efficacy in the treatment of infections in diabetic patients. However, daptomycin degrades in 5% glucose solution, and data on the efficacy of daptomycin in hyperglycemic patients are limited. Therefore, we investigated the effect of high levels of blood glucose on the efficacy and concentration of daptomycin. The efficacy of simulated human exposure to daptomycin against S. aureus was compared in a neutropenic murine thigh model, with and without hyperglycemia. A clinically isolated MRSA strain and S. aureus ATCC25923 standard strain were used. Daptomycin concentrations, in the serum and at the infected site, were preliminarily analyzed using the high-performance liquid chromatography assay. Even in hyperglycemic mice, the mean concentration of daptomycin in hyperglycemic mice was equivalent to that in untreated mice within the physiological blood glucose levels. Additionally, the efficacy of daptomycin against MRSA was equal to that observed in the untreated and hyperglycemic mice. Based on similar studies using S. aureus ATCC25923, the efficacy in hyperglycemic mice was equal to or greater than that observed in untreated mice. In conclusion, daptomycin is an alternative therapeutic option in diabetic mice with serious staphylococcal infections, regardless of blood glucose control in this animal model.

Estimating the national cost burden of in-hospital needlestick injuries among healthcare workers in Japan.

BACKGROUND: Needlestick injury (NSI) is one of the most burdensome professional hazards in any medical setting; it can lead to transmission of fatal infectious diseases, such as hepatitis B, hepatitis C and human immunodeficiency virus. In the United States, the annual cost burden was estimated as somewhere between $118 million to $591 million; in the United Kingdom it is approximated to be £500,000 (US$919,117.65) per the National Health Service. METHOD: This is the first published paper on the national cost burden of NSIs in Japan. A systematic literature review was conducted to review previous study design in global studies and to extract parameter values from Japanese studies. We conducted abstract searches through PubMed and the Japan Medical Abstracts Society (Ichushi), together with grey literature and snowball searches. A simple economic model was developed to calculate cost burden of NSIs from a societal perspective over a one-year time horizon. We assumed all NSIs are reported and perfect adherence in post NSI management that presented in the labour compensation scheme. Local guidelines were also referenced to extract resource utilization. Lastly, a deterministic sensitivity analysis was conducted and a scenario analysis which considered a payer perspective was also included. RESULT AND CONCLUSION: The national cost burden of in-hospital NSIs is estimated as ¥33.4 billion (US$302 million) annually, based on an average cost per NSI of ¥63,711 (US$577) and number of NSIs at 525,000/year. 70% of the cost is due to initial laboratory tests, followed by productivity loss, estimated at 20% of the total cost. Cost of contaminated NSIs remains at 5% of the total cost. Change in number of NSIs significantly influences outcomes. Variation in post-exposure management practices suggests a need for NSI specific National guidelines and holistic labour compensation scheme development in Japan.

Tradescantia pallida extract inhibits biofilm formation in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is capable of biofilm formation. In this study, we investigated the effects of aqueous Tradescantia pallida extract on Pseudomonas aeruginosa growth and biofilm formation. Aqueous Tradescantia pallida extracts significantly inhibited both bacterial growth and biofilm formation. However, methanolic Tradescantia pallida extracts inhibited neither. Aqueous Tradescantia pallida extracts were deactivated by heating but were not deactivated by light exposure. The ingredients retained the inhibitory effect on the bacterial growth and biofilm formation after ultrafiltration of aqueous Tradescantia pallida extract. Furthermore, polyphenol-rich Tradescantia pallida extracts inhibited bacterial growth, thus, polyphenols are possible to be an active ingredient. We observed the biofilm by scanning electron microscopy, and quantitative and qualitative differences in the biofilm and cells morphology. Interestingly, the biofilm treated aqueous Tradescantia pallida extracts remained premature. We postulated that premature biofilm formation was due to the inhibition of swarming motility. Indeed, aqueous Tradescantia pallida extracts inhibited swarming motility. These results demonstrate that Peudomonas aeruginosa growth and biofilm formation are inhibited by aqueous Tradescantia pallida extracts.

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 2014: 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, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2014. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period between January 2014 and April 2015 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical Laboratory Standards Institute. Susceptibility testing was evaluated in 1534 strains (335 Staphylococcus aureus, 264 Streptococcus pneumoniae, 29 Streptococcus pyogenes, 281 Haemophilus influenzae, 164 Moraxella catarrhalis, 207 Klebsiella pneumoniae, and 254 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was 43.6%, and those of penicillin-susceptible S. pneumoniae was 100%. Among H. influenzae, 8.2% of them were found to be ß-lactamase-producing ampicillin-resistant strains, and 49.1% 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 9.2% and 0.4%, respectively.

Metronidazole-induced encephalopathy caused by hyperbaric oxygen therapy in a patient with mandibular osteomyelitis.

Metronidazole (MNZ) is prescribed for the treatment of infection caused by anaerobic bacteria and protozoa. Metronidazole-induced encephalopathy (MIE) has been known to be a side-effect, although its onset ratio is unclear. However, to the best of our knowledge, MIE associated with hyperbaric oxygen therapy (HBO) has not been previously reported. Here, we present the case of a 68-year-old man with mandibular osteomyelitis who received metronidazole for 49 days and received five times HBO therapy. He visited our hospital for evaluation and treatment of peripheral neuropathy, speech disturbance, nausea, and disturbance of gait after 47 days of initiating metronidazole treatment. Brain magnetic resonance imaging revealed hyperintense lesions in the cerebellar dentate nuclei, which was consistent with MIE. The patient's ataxic symptoms improved in 15 days after the discontinuation of MNZ. This is the first report demonstrating case of MIE could be related with HBO, as far as we had searched.

Antimicrobial activity of solithromycin and levofloxacin against a murine pneumonia mixed-infection model caused by Streptococcus pneumoniae and anaerobic bacteria.

INTRODUCTION: Solithromycin is a novel fluoroketolide developed to treat pneumonia. But, few studies evaluating its antimicrobial activity against S. pneumoniae in a mixed-infection model with anaerobes are available, while community-acquired pneumonia can involve mixed-infection of Streptococcus pneumoniae and anaerobic bacteria. This study evaluated the antimicrobial activity of solithromycin against macrolide-resistant S. pneumoniae and anaerobic bacteria with a murine pneumonia mixed-infection model. MATERIAL AND METHODS: We evaluated antimicrobial activity of solithromycin (10 and 20 mg/kg) and levofloxacin (126 mg/kg) against S. pneumoniae with a three-point mutation in penicillin-binding protein and an ermB gene, and Parvimonas micra. Antimicrobial efficacy was calculated for each isolate as the change in bacterial count (Δlog10 CFU/mL) obtained in the treated mice after 24 h compared with the count in the starting control animals. RESULTS: The solithromycin and levofloxacin minimum inhibitory concentrations (MICs) for S. pneumoniae were 0.03 and 0.5 µg/mL, respectively. The solithromycin and levofloxacin MICs for P. micra were 0.015 and 0.12 µg/mL, respectively. In a mixed-infection model, solithromycin showed significantly higher antimicrobial activity against S. pneumoniae than levofloxacin (solithromycin 20 mg/kg; -2.87 ± 1.33 log10 CFU/mL vs. levofloxacin; -1.35 ± 0.37 log10 CFU/mL, p = 0.0397). Similarly, solithromycin showed significantly higher antimicrobial activity against P. micra than levofloxacin (solithromycin 20 mg/kg; -2.78 ± 0.98 log10 CFU/mL vs. levofloxacin; -1.57 ± 0.47 log10 CFU/mL, p = 0.0400). DISCUSSION: Solithromycin showed higher antimicrobial activities against macrolide-resistant S. pneumoniae and P. micra than levofloxacin, even though they were coexisted in murine lung tissue. Our results suggest that solithromycin could be effective for pneumonia patients due to S. pneumoniae to reduce bacterial density in lung tissue.

Considerations about the Use of a Loading Dose of Daptomycin in a Neutropenic Murine Thigh Infection Model with Methicillin-Resistant Staphylococcus aureus Infection.

Previous clinical studies have showed the clinical benefits of the initiation of treatment with a daptomycin (DAP) loading dose, but only a few studies have evaluated its antimicrobial benefits. We evaluated the efficacy of a DAP loading dose against methicillin-resistant Staphylococcus aureus (MRSA) infections in a neutropenic murine thigh infection model. Three MRSA isolates (DAP MIC: 0.5, 1, and 2 mg/L) were tested. Four DAP regimens simulating human concentration-time profiles, i.e., (i) day 1: 8 mg/kg and day 2: 6 mg/kg, (ii) days 1 and 2: 6 mg/kg/day, (iii) day 1: 8 mg/kg and day 2: 4 mg/kg, and (iv) days 1 and 2: 4 mg/kg/day, were administered to the mice. Efficacy was calculated as the change in bacterial density. DAP loading-dose regimen iii showed greater antimicrobial activity against MRSA with MIC 1 mg/L than nonloading regimen iv (-3.10 ± 0.63 vs. -0.71 ± 0.34 log10 CFU; p < 0.01). Loading-dose regimen iii achieved greater log10 CFU changes than nonloading regimen ii, while the total DAP dose for 2 days was the same (-3.10 ± 0.63 vs. -1.46 ± 0.48 log10 CFU; p < 0.05). DAP loading-dose regimen iii showed enhanced antimicrobial activity against MRSA with DAP MIC 0.5 mg/L when compared with nonloading regimen iv. However, loading-dose regimens i and iii did not reduce bacterial density for MRSA with DAP MIC 2 mg/L. Our data suggest that a DAP loading-dose regimen would be an advantageous procedure for patients infected with MRSA with DAP MIC ≤1 mg/L.

Efficacy of tedizolid against methicillin-resistant Staphylococcus aureus and Peptostreptococcus anaerobius in thigh mixed-infection mouse model.

OBJECTIVE: The purpose of this study is to compare the antimicrobial activity of human simulated exposures of tedizolid 200 mg daily, and linezolid 600 mg every 12 h for the treatment of complicated skin and skin structure infection (cSSSI) caused by MRSA and Peptostreptococcus anaerobius in both the neutropenic mice thigh mixed-infection models. MATERIAL AND METHOD: Tedizolid phosphate and linezolid were used for all in vivo testing. A total of one MRSA and two P. anaerobius isolates were utilized. Antimicrobial efficacy was calculated for each isolate as the change in bacterial numbers (Δlog10 CFU/ml) obtained in the treated mice after 24 h compared with the numbers in the starting control animals (0 h). RESULTS: The tedizolid and linezolid MICs for MRSA was 0.25 and 2 µg/ml. Tedizolid MIC for P. anaerobius was 0.12 µg/ml, and linezolid MICs for two P. anaerobius isolates were 0.5 and 1 µg/ml. In mixed infection model, tedizolid therapy showed similar antimicrobial activities for one MRSA and two P. anaerobius isolates evaluated, compared with linezolid therapy. Additionally, when comparing the activity of tedizolid and linezolid monotherapy between single infection and mixed infection model, antimicrobial activities of both antimicrobials were attenuated when mixed infection model was used. CONCLUSION: In the neutropenic murine thigh infection model, human simulated exposures of tedizolid and linezolid resulted in similar efficacies against MRSA, even though single and mixed infection models were used. These data support the clinical utility of tedizolid for use against MRSA and P. anaerobius in the treatment of cSSSI.

Colistin loading dose enhanced antimicrobial activity for in vivo mouse thigh infection model with Pseudomonas aeruginosa with highly antimicrobial resistant.

This is the first report to test the loading dosage of colistin against Pseudomonas aeruginosa, including MDRP. Using in vivo murine thigh infection model, in the loading dosage regimen (Day 1:50 mg/kg q12 h, Day 2-3: 25 mg/kg q12 h) group, 5 to 6 log10 CFU/ml reduction compared with control were observed for both strains of P. aeruginosa with colistin MIC 0.5 and 1 µg/mL at 72 h. But, similar reduction was observed for the strains with colistin MIC 0.5 µg/mL only in normal dosage regimen (Day 1-3: 25 mg/kg q12 h) group. For P. aeruginosa with colistin MIC 1 µg/mL, colistin loading dosage regimens showed greater antimicrobial activity than that of without loading dosage group (p < 0.05). These data suggest that the colistin loading regimen would be one of the useful options for P. aeruginosa with antimicrobial resistance infection treatment.

Proposed breakpoint of piperacillin/tazobactam against extended spectrum ß-lactamases producing bacteria in bacteremia.

The isolation rate of extended-spectrum ß-lactamase (ESBL)-producing bacteria have been increasing in Japan. While the efficacy of piperacillin/tazobactam (PIPC/TAZ) for ESBL-producing bacteria is controversial, carbapenems have generally been shown to be effective. The aim of this study was to determine whether the current Clinical and Laboratory Standards Institute susceptibility breakpoint of ≤16/4 µg/mL PIPC/TAZ predicts the clinical usefulness for bacteremia caused by ESBL-producing Enterobacteriaceae. We retrospectively investigated 35 patients with bacteremia caused by Enterobacteriaceae producing ESBLs treated with PIPC/TAZ monotherapy. The microbiological and clinical efficacy with PIPC/TAZ minimum inhibitory concentrations (MICs) of ≤16/4 µg/mL was better than that with MICs ≥ 32/4 µg/mL. In contrast, MICs ≤8/4 µg/mL showed significantly higher microbiological and clinical efficacy compared to that of MICs ≥16/4 µg/mL (P < 0.05). These results suggest that 8/4 µg/mL PIPC/TAZ MIC is recommended as a breakpoint for bacteremia caused by ESBL-producing Enterobacteriaceae in Japan, although the current CLSI breakpoint is also useful.

Antifungal susceptibilities of Candida species isolated from the patients with vaginal candidiasis.

There have been the current Japanese data on susceptibility testing for Candida isolates from vaginal candidiasis. The in vitro activities of therapeutic antifungal drugs for vulvovaginal candidiasis (VVC); miconazole (MCZ), itraconazole (ITCZ), fluconazole (FLCZ), clotrimazole (CTZ), oxiconazole (OCZ), isoconazole (ICZ) and bifonazole (BFZ) against vaginal isolates. Fifty-four strains Candida albicans and 19 strains of Candida glabrata were evaluated using a broth microdilution method specified by Clinical Laboratories Standard Institute (CLSI) document M27-A3. The MIC90 of each drug, MCZ, ITCZ, FLCZ, CTZ, OCZ, ICZ and BFZ, against C. albicans and C. glabrata isolates were 0.25, 0.12, 1, 0.06, 0.12, 0.12 and 1 µg/ml and 1, 1, 8, 0.5, 0.25, 0.5 and 1 µg/ml respectively. The activities of these drugs, except for BFZ, against C. glabrata were lower than that of C. albicans. There was one azole-resistant isolate in C. glabrata of which MIC of FLCZ is > 64 µg/ml and this isolate had cross resistance to other antifungal drugs tested. These results suggest that antifungal drugs for treatment of VVC continues to have potent antifungal activities against C. albicans and C. glabrata isolates from vaginitis. CTZ, OCZ and ICZ susceptibility of FLCZ low susceptibility C. glabrata are relatively higher than MCZ, ITCZ and FLCZ.

Characterization of Piperacillin/Tazobactam-Resistant Klebsiella oxytoca Recovered from a Nosocomial Outbreak.

We characterized 12 clinical isolates of Klebsiella oxytoca with the extended-spectrum ß-lactamase (ESBL) phenotype (high minimum inhibitory concentration [MIC] values of ceftriaxone) recovered over 9 months at a university hospital in Japan. To determine the clonality of the isolates, we used pulsed-field gel electrophoresis (PFGE), multi-locus sequence typing (MLST), and PCR analyses to detect blaRBI, which encodes the ß-lactamase RbiA, OXY-2-4 with overproduce-type promoter. Moreover, we performed the isoelectric focusing (IEF) of ß-lactamases, and the determination of the MICs of ß-lactams including piperacillin/tazobactam for 12 clinical isolates and E. coli HB101 with pKOB23, which contains blaRBI, by the agar dilution method. Finally, we performed the initial screening and phenotypic confirmatory tests for ESBLs. Each of the 12 clinical isolates had an identical PFGE pulsotype and MLST sequence type (ST9). All 12 clinical isolates harbored identical blaRBI. The IEF revealed that the clinical isolate produced only one ß-lactamase. E. coli HB101 (pKOB23) and all 12 isolates demonstrated equally resistance to piperacillin/tazobactam (MICs, >128 µg/ml). The phenotypic confirmatory test after the initial screening test for ESBLs can discriminate ß-lactamase RbiA-producing K. oxytoca from ß-lactamase CTX-M-producing K. oxytoca. Twelve clinical isolates of K. oxytoca, which were recovered from an outbreak at one university hospital, had identical genotypes and produced ß-lactamase RbiA that conferred resistance to piperacillin/tazobactam. In order to detect K. oxytoca isolates that produce RbiA to promote research concerning ß-lactamase RbiA-producing K. oxytoca, the phenotypic confirmatory test after the initial screening test for ESBLs would be useful.

Anti-Androgenic Activity of Icarisid II from Epimedium Herb in Prostate Cancer LNCaP Cells.

Anti-androgens are regarded as potential therapeutic agents for the treatment of prostate cancer. We determined that an epimedium herb (EH) extract exhibited anti-androgenic activity in a luciferase assay using androgen receptor-positive prostate cancer LNCaP cells. Nine EH-derived flavonoids were examined. The results identified icarisid II as a very potent anti-androgenic EH-derived flavonoid. A quantitative RT-PCR analysis confirmed that the flavonol suppressed the expression of the androgen-responsive KLK3 gene.

Efficacy and safety of metronidazole injection for the treatment of infectious peritonitis, abdominal abscess and pelvic inflammatory diseases in Japan.

Although metronidazole (MNZ) has been used worldwide for more than 4 decades as a standard therapy for trichomoniasis, anaerobic and amebic infections, resistance to MNZ is still low. MNZ is available as oral, intravenous, and vaginal formulations, but the intravenous formulation of MNZ has not been approved in Japan. We conducted a phase 3 study to evaluate the efficacy and safety of intravenous MNZ combined with ceftriaxone (CTRX) in Japanese subjects with infectious peritonitis, abdominal abscess or pelvic inflammatory diseases (PIDs) to obtain regulatory approval. A combination of MNZ/CTRX at doses of 500 mg 3 or 4 times a day/1 or 2 g twice a day was administered intravenously to a total of 38 hospitalized subjects. MNZ/CTRX was well tolerated and exhibited excellent clinical and bacteriological efficacy with clinical efficacy rates of 100% (20/20) in infectious peritonitis or abdominal abscess subjects and 90.0% (9/10) in PID subjects, and the eradication rates in infectious peritonitis or abdominal abscess subjects and PID subjects were 100% (16/16) and 100% (4/4), respectively, at the test of cure. MNZ/CTRX was effective in 1 subject in whom a metallo-ß-lactamase-producing Bacteroides fragilis strain (MIC of MNZ, 2 µg/ml) was identified. The most common treatment-related adverse event was diarrhea (23.7%), followed by nausea (5.3%). No new safety signals were identified. MNZ/CTRX demonstrated excellent efficacy and was well tolerated in Japanese infectious peritonitis, abdominal abscess and PID subjects. This treatment regimen can be useful for anaerobic infections. Clinical registration number: NCT01473836.

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.

Open-label study to evaluate the pharmacodynamics, clinical efficacy, and safety of meropenem for adult bacterial meningitis in Japan.

The aim of this study was to assess the efficacy, safety, and concentration of meropenem in cerebrospinal fluid when meropenem (2 g every 8 h) was administered to Japanese adult patients with bacterial meningitis. Five Japanese patients (mean age 60.6 years [range 35-71]) were enrolled. Infection with Streptococcus pneumoniae (three patients), Streptococcus salivarius (one patient), and Staphylococcus aureus (one patient) was confirmed by cerebrospinal fluid culture. Meropenem (2 g every 8 h) was administered to all five patients. Treatment duration ranged from 14 to 28 days (mean 22.6 days). All the patients were successfully treated. The concentration of meropenem in cerebrospinal fluid ranged from 0.27 to 6.40 µg/ml up to 8.47 h and was over 1 µg/ml 3 h after starting meropenem infusion. In each patient, the present study confirmed for the first time that the concentration of meropenem in cerebrospinal fluid exceeded the minimal inhibitory concentration for these pathogens. Eleven clinical and laboratory adverse events considered to be related to meropenem were observed in all patients, but no serious adverse event and no discontinuance of treatment due to adverse events occurred. Thus meropenem appeared to be a well-tolerated and effective agent for Japanese adult patients with bacterial meningitis. 2 g every 8 h of meropenem was delivered to CSF and its concentration was exceed in MICs for the detected pathogens.

Azithromycin attenuates lung inflammation in a mouse model of ventilator-associated pneumonia by multidrug-resistant Acinetobacter baumannii.

Acinetobacter baumannii is one of the main pathogens that cause ventilator-associated pneumonia (VAP) and is associated with a high rate of mortality. Little is known about the efficacy of macrolides against A. baumannii. In order to confirm the efficacy of azithromycin (AZM) against VAP caused by multidrug-resistant A. baumannii (MDRAB), we used a mouse model that mimics VAP by placement of a plastic tube in the bronchus. AZM (10 and 100 mg/kg of body weight) was administered subcutaneously every 24 h beginning at 3 h after inoculation. Phosphate-buffered saline was administered as the control. Survival was evaluated over 7 days. At 48 h postinfection, mice were sacrificed and the numbers of viable bacteria in lungs and bronchoalveolar lavage fluid were compared. Histopathological analysis of lung specimens was also performed. The treatment groups displayed significantly longer survival than the control group (P < 0.05). AZM did not have an antimicrobial effect. Histopathological examination of lung specimens indicated that the progression of lung inflammation was prevented in the AZM-treated groups. Furthermore, total cell and neutrophil counts, as well as cytokine levels, in bronchoalveolar lavage fluid were significantly decreased (P < 0.05) in the AZM-treated groups. AZM may have a role for the treatment of VAP with MDRAB because of its anti-inflammatory effects.

Efficacy and safety of intravenous daptomycin in Japanese patients with skin and soft tissue infections.

Daptomycin is a lipopeptide antibiotic active against gram-positive organisms and recently approved for marketing in Japan. This study investigates the efficacy and safety of daptomycin in Japanese patients with skin and soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) for regulatory filing in Japan. Overall, 111 Japanese patients with SSTI were randomized in this open-label, randomized, active-comparator controlled, parallel-group, multicenter, phase III study. Patients received intravenous daptomycin 4 mg/kg once daily or vancomycin 1 g twice daily for 7-14 days. Efficacy was determined by a blinded Efficacy Adjudication Committee. Among patients with SSTIs caused by MRSA, 81.8 % (95 % CI, 69.1-90.9) of daptomycin recipients and 84.2 % (95 % CI, 60.4-96.6) of vancomycin recipients achieved a successful clinical response at the test-of-cure (TOC) visit. The microbiological success rate against MRSA at the TOC visit was 56.4 % (95 % CI, 42.3-69.7) with daptomycin and 47.4 % (95 % CI, 24.4-71.1) with vancomycin. Daptomycin was generally well tolerated; most adverse events were of mild to moderate severity. The measurement of daptomycin concentration in plasma revealed that patients with mild or moderate impaired renal function showed similar pharmacokinetics profiles to patients with normal renal function. Clinical and microbiological responses, stratified by baseline MRSA susceptibility, suggested that patients infected with MRSA of higher daptomycin MIC showed a trend of lower clinical success with a P value of 0.052 by Cochran-Armitage test. Daptomycin was clinically and microbiologically effective for the treatment of MRSA-associated SSTIs in Japanese patients.