The Japanese Surveillance Committee conducted a second nationwide surveillance of antimicrobial susceptibility patterns of uropathogens responsible for acute uncomplicated cystitis (AUC) in ...premenopausal patients aged 16–40 years old at 31 hospitals throughout Japan from March 2015 to February 2016. In this study, the susceptibility of causative bacteria (Escherichia coli, Klebsiella pneumoniae, Staphylococcus saprophyticus) for various antimicrobial agents was investigated by isolation and culturing of organisms obtained from urine samples. In total, 324 strains were isolated from 361 patients, including E. coli (n = 220, 67.9%), S. saprophyticus (n = 36, 11.1%), and K. pneumoniae (n = 7, 2.2%). The minimum inhibitory concentrations (MICs) of 20 antibacterial agents for these strains were determined according to the Clinical and Laboratory Standards Institute (CLSI) manual. At least 93% of the E. coli isolates showed susceptibility to fluoroquinolones and cephalosporins, whereas 100% of the S. saprophyticus isolates showed susceptibility to fluoroquinolones and aminoglycosides. The proportions of fluoroquinolone-resistant and extended-spectrum β-lactamase (ESBL)-producing E. coli strains were 6.4% (13/220) and 4.1% (9/220), respectively. The antimicrobial susceptibility of K. pneumoniae was retained during the surveillance period, while no multidrug-resistant strains were identified.
In summary, antimicrobial susceptibility results of our second nationwide surveillance did not differ significantly from those of the first surveillance. Especially the numbers of fluoroquinolone-resistant and ESBL-producing E. coli strains were not increased in premenopausal patients with AUC in Japan.
Ketamine is metabolized by cytochrome P450 (CYP) leading to production of pharmacologically active products and contributing to drug excretion. We identified the CYP enzymes involved in the ...N-demethylation of ketamine enantiomers using pooled human liver microsomes and microsomes from human B-lymphoblastoid cells that expressed CYP enzymes. The kinetic data in human liver microsomes for the (R)- and (S)-ketamine N-demethylase activities could be analyzed as two-enzyme systems. The K(m) values were 31 and 496 microM for (R)-ketamine, and 24 and 444 microM for (S)-ketamine. Among the 12 cDNA-expressed CYP enzymes examined, CYP2B6, CYP2C9, and CYP3A4 showed high activities for the N-demethylation of both enantiomers at the substrate concentration of 1 mM. CYP2B6 had the lowest K(m) value for the N-demethylation of (R)- and (S)-ketamine (74 and 44 microM, respectively). Also, the intrinsic clearance (CL(int): V(max)/K(m)) of CYP2B6 for the N-demethylation of both enantiomers were 7 to 13 times higher than those of CYP2C9 and CYP3A4. Orphenadrine (CYP2B6 inhibitor, 500 microM) and sulfaphenazole (CYP2C9 inhibitor, 100 microM) inhibited the N-demethylase activities for both enantiomers (5 microM) in human liver microsomes by 60 to 70%, whereas cyclosporin A (CYP3A4 inhibitor, 100 microM) failed to inhibit these activities. In addition, the anti-CYP2B6 antibody inhibited these activities in human liver microsomes by 80%, whereas anti-CYP2C antibody and anti-CYP3A4 antibody failed to inhibit these activities. These results suggest that the high affinity/low capacity enzyme in human liver microsomes is mediated by CYP2B6, and the low affinity/high capacity enzyme is mediated by CYP2C9 and CYP3A4. CYP2B6 mainly mediates the N-demethylation of (R)- and (S)-ketamine in human liver microsomes at therapeutic concentrations (5 microM).
Abstract 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 β-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.
ABSTRACT
Kaposi's varicelliform eruption is the most important problem in treating patients with atopic dermatitis (AD) with tacrolimus ointment. It has been considered that Kaposi's varicelliform ...eruption occurs due to decreased levels of interleukin (IL)‐18. The aim of this study was to examine the relationship between Kaposi's varicelliform eruption and genetic polymorphisms in the IL‐18 gene. IL‐18 gene promoter polymorphisms were analyzed in 21 AD patients treated with tacrolimus ointment and in 100 healthy volunteers. Six AD patients with Kaposi's varicelliform eruption during the treatment with tacrolimus ointment showed significantly higher frequency in G‐to‐C mutations at the IL‐18 gene promoter region –137 compared with 15 AD patients without Kaposi's varicelliform eruption. The 15 AD patients without Kaposi's varicelliform eruption as well as 100 healthy volunteers did not have mutations of G‐to‐C at the IL‐18 gene promoter region –137. These results suggest that the onset of Kaposi's varicelliform eruption following the treatment with tacrolimus ointment is associated with the mutation of G‐to‐C in the IL‐18 gene promoter region –137, and that caution is required when using tacrolimus ointment for treating AD patients with this mutation.
We conducted a retrospective study of the occurrence of deep venous thrombosis (DVT) following mini-posterior total hip arthroplasty (THA) in Japanese patients. From May 2004 to December 2009 ...mini-posterior THA was performed on 1659 cases, of whom 603 cases didn't receive anticoagulants (Group 1), 547 cases received 2.5 mg percutaneous injection of fondaparinux (a factor Xa inhibitor) daily for 7 days starting the day after surgery (Group 2), and 509 cases received 2000IU percutaneous injection of enoxaparin (low-molecular-weight heparin) twice daily for 7 days starting the day after surgery (Group 3). The baseline characteristics were very similar in each group. All patients started walking the day after surgery, were advised to wear graduated compression stockings for six weeks after the operation, and used a foot pump for 3 hours a day postoperatively for several days. A week after surgery Duplex ultrasound with colour-flow Doppler imaging of the lower extremities was performed. The occurrence of DVT was significantly different between Groups 1, 2, and 3 (p<0.001): 57 cases (9.5%), 4 cases (0.7%), and 0 cases (0%), respectively. No patients of any group had clinically detected pulmonary emboli. In this study we showed that adding anticoagulants with foot pumps further reduced the incidence of DVT, which seldom occurs following less invasive mini-posterior THA combined with early mobilisation, foot pumps, and anticoagulants.
The oxidative metabolism of cinnarizine (E)-1-(diphenylmethyl)-4-(3-phenyl-2-propyl)piperazine, CZ and flunarizine (E)-1-bis(4-fluorophenyl)methyl4-(3-phenyl-2-propyl)piperazine, FZ was examined in ...microsomes from lymphoblastoid cells that expressed human cytochrome P450 (CYP) enzymes. Among 10 kinds of CYP enzymes examined, only CYP2D6 catalyzed p-hydroxylation of the cinnamyl phenyl ring of CZ (C-2 formation) and FZ (F-2 formation), and only CYP2B6 exhibited activity for p-hydroxylation (C-4 formation) of the diphenylmethyl group of CZ at a substrate concentration of 50 μM. On the other hand, CYP2C9 together with CYP1A1, -1A2 and/or -2A6 mediated N-desalkylation at the 1- and 4-positions of the piperazine ring of the two drugs that formed C-1 and C-3 from CZ and F-1 and F-3 from FZ, respectively, whereas CYP2C8, -2C19, -2E1 or -3A4 did not show detectable activity for these reactions under the conditions used. We then examined kinetics for the oxidative metabolism of CZ and FZ using CYP2B6 and -2D6 that have considerable activities. CYP2D6 with Km values of 2 to 4 μM had intrinsic clearance values (Vmax/Km) of 0.31 and 0.14 ml/min/nmol CYP for C-2 and F-2 formation, respectively, while CYP2B6 with a Km value of 17 μM exhibited the clearance value of 0.10 ml/min/nmol CYP for C-4 formation. These results suggest that CYP2D6 mainly mediates p-hydroxylation of the cinnamyl phenyl rings of CZ and FZ, and CYP2B6 mediates that of the diphenylmethyl group of CZ.
By using lactose colored with erythrocin, we examined the effect of particle size on mixing degree during the preparation of triturations with a mortar and pestle. We used powders with different ...distributions of particle sizes, i.e., powder that passed through 32-mesh but was trapped on a 42-mesh sieve (32/42-mesh powder), powder that passed through a 42-mesh sieve but was trapped on a 60-mesh sieve (42/60-mesh powder), powder that passed through a 60-mesh sieve but was trapped on a 100-mesh sieve (60/100-mesh powder), and powder that passes through a 100-mesh sieve (>100-mesh powder). The mixing degree of colored powder and non-colored powder whose distribution of particle sizes was the same as that of the colored powder was excellent. The coefficient of variation (CV) value of the mixing degree was 6.08% after 40 rotations when colored powder was mixed with non-colored powder that both passed through a 100-mesh sieve. The CV value of the mixing degree was low in the case of mixing of colored and non-colored powders with different particle size distributions. After mixing, about 50% of 42/60-mesh powder had become smaller particles, whereas the distribution of particle sizes was not influenced by the mixing of 60/100-mesh powder. It was suggested that the mixing degree is affected by distribution of particle sizes. It may be important to determine the mixing degrees for drugs with narrow therapeutic ranges.
By using lactose colored with erythrocin, we investigated the effects of mixing methods on mixing degree during the preparation of trituration with a mortar and pestle. The extent of powder dilution ...was set to 4 to 64 fold in the experiments. We compared the results obtained by using two methods: (1) one-step mixing of powders after addition of diluents and (2) gradual mixing of powders after addition of diluents. As diluents, we used crystallized lactose and powdered lactose for the preparation of trituration. In the preparation of 64-fold trituration, an excellent degree of mixing was obtained, with CV values of less than 6.08%, for both preparation methods and for the two kinds of diluents. The mixing of two kinds of powders whose distributions of particle sizes were similar resulted in much better degree of mixing, with CV values of less than 3.0%. However, the concentration of principal agents in 64-fold trituration was reduced by 20% due to the adsorption of dye to the apparatus. Under conditions in which a much higher dilution rate and/or much better degree of dilution was required, it must be necessary to dilute powders with considering their physicality and to determine the concentrations of principal agents after the mixing.
A stereoselective high-performance liquid chromatographic method for the determination of the enantiomers of ketamine and its active metabolite, norketamine, in human plasma is described. The ...compounds were extracted from plasma by liquid–liquid extraction three times in a combination of cyclohexane with 2.5
M NaOH, 1 m
M HCl and 1
M carbonate buffer. Stereoselective separation was achieved on a Chiralcel OD column with a mobile phase of
n-hexane–2-propanol (98:2, v/v). The detection wavelength was 215 nm. The lower limits of the determination of the method were 5 ng/ml for ketamine and 10 ng/ml for norketamine. The intra- and inter-day coefficients of variation ranged from 2.9 to 9.8% and from 3.4 to 10.7% for all compounds, respectively. The method was sensitive and sufficiently reproducible for stereoselective monitoring of ketamine and norketamine in human plasma during pharmacokinetic studies after the administration of ketamine for analgesia.
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