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Background: In Japan, therapeutic agents are often administered through the side tube of a central venous line or mixed with a total parenteral nutrition (TPN) infusion. This is expected to result in the mixture of three drugs in the infusion line: the infusion product for TPN, the fat emulsion, and the therapeutic agent. Therefore, we investigated whether various therapeutic agents affect the particle size of the fat emulsion. Methods: In model of administration A, the TPN infusion formulation was administered through the main tube, and the fat emulsion and therapeutic agents were simultaneously administered through the side tube; 21 therapeutic agents were used. In model of administration B, the TPN infusion formulation mixed with therapeutic agents was administered through the main tube, and the fat emulsion was simultaneously administered through the side tube; 20 therapeutic agents were used. The number of fine particles for each particle size range in the mixed solution was measured over time using a light-shielding automatic fine-particle measuring device. Results: In model A, the number of fine particles in the fat emulsion changed rapidly for five therapeutic agents and slowly for two therapeutic agents. In model B, this change occurred drastically for five therapeutic agents and slowly for one therapeutic agent. Conclusions: Some therapeutic agents may contribute to fat particle aggregation. Therefore, these therapeutic agents should not be concurrently administered with fat emulsions.

Background: We investigated the extent of growth of microorganisms with simultaneous administration of lipid emulsions with infusions for Total Parenteral Nutrition (TPN), assuming that the lipid emulsions contaminated with microorganisms are stagnant in a closed-type infusion device. We also investigated if bacterial growth can be prevented in the infusion device by flushing the inside of the infusion device with saline solution after the administration of lipid emulsion from the side tube in vitro setting. Methods: We made a preparation by adding Escherichia coli to the lipid emulsion and started the infusion simultaneously with the infusion solution for TPN and lipid emulsion with the piggyback method. Immediately after the completion of lipid emulsion infusion, we conducted flushing with saline solution. The volume of saline solution was none, 5, 10, or 20 mL at a flow rate of 1 mL/s. Infusion solution that was stagnant in the infusion device was collected immediately before completing the lipid emulsion infusion and 20 h after flushing, i.e., 24 h after starting the infusion for TPN, and the number of viable bacteria was determined. Results: The number of viable E. coli increased in the infusion device of all three species used in this experiment 24 h after starting the lipid emulsion infusion without flushing. We found that bacterial growth could be prevented through flushing with saline solution after the completion of lipid emulsion infusion and flushing out the stagnant infusion solution in the closed-type infusion device. Conclusions: We found that if E. coli was present in the closed-type infusion device, it would multiply. We also found that the number of viable bacteria varied according to the variety and internal structure of the closed-type infusion device as well as the liquid volume used for flushing, although flushing can prevent the growth of microorganisms. Proper management and manipulation of infusion is required to prevent infection.

Deterioration of drugs due to light exposure is one of the major concerns, especially regarding protection of high-calorie infusion solutions, lightproof covers are used in hospitals. In the absence of any set standards regarding their usage, they are often reused. This study aimed to investigate bacterial contamination of lightproof covers used in hospital wards. For this, lightproof covers which had been used or stored in wards were collected and bacterial cultures were carried out from them. Examination of the cultures revealed that bacteria were present in the used lightproof covers. The bacterial species detected in the used lightproof covers were Bacillus species Coagulase-negative Staphylococci (CNS) and Methicillin-resistant Staphylococcus aureus (MRSA). Bacillus species and CNS were also detected in lightproof covers stored in wards, whereas MRSA was not detected. Intestinal bacteria were detected in only one lightproof cover. However, no bacteria were detected from either inside or outside of the unused lightproof covers that were stored in the drugs department. After allowing the unused lightproof covers stored in the drugs department to stand for 24 h, Bacillus species and CNS were detected in only one of the covers, whereas no bacteria was detected in other covers. These results indicate that there is a risk of bacterial contamination in the reuse of lightproof covers and that they should either be disposed off properly after usage or hand, finger disinfectants should be used while handling them to prevent any possible contamination.

What is known and objective In our previous studies, we developed a cross-resistance rate (CRR) correlation diagram (CRR diagram) that visually captures the magnitude of CRRs between antimicrobials using scatter plots. We used asymmetric multidimensional scaling (MDS) to transform cross-resistance similarities between antimicrobials into a 2-dimensional map and attempted to visually express them. We also explored the antibiograms of Pseudomonas aeruginosa before and after the transfer to newly built hospitals, and we determined by the CRR diagram that the CRRs among β-lactam antimicrobials other than carbapenems decreased substantially with the facility transfer. The present study tests whether the analysis of CRRs by asymmetric MDS can be used as new visual information that is easy for healthcare professionals to understand. Method We tested the impact of changes in the nosocomial environment due to institutional transfers on CRRs among antimicrobials in asymmetric MDS, as well as contrasted the asymmetric MDS map and CRR diagram. Results and discussion In the asymmetric MDS map, antimicrobial groups with the same mechanism of action were displayed close together, and antimicrobial groups with different mechanisms of action were displayed separately. The asymmetric MDS map drawn solely for antimicrobials belonging to the group with the same mechanism of action showed similarities to the CRR diagram. Also, the distance of each antimicrobial to other antimicrobials shown in the asymmetric MDS map was negatively correlated with the CRRs for them against that antimicrobial. What is new and conclusion The asymmetric MDS map expresses the dissimilarity as distances between agents, and there are no meanings or units on the ordinate and abscissa axes of the output map. In contrast, the CRR diagram expresses the antimicrobials' resistance status as values, such as resistance rate and CRR. By analysing the CRRs in the asymmetric MDS, it is feasible to visually recognize cross-resistance similarities between antimicrobial groups as distances. The use of the asymmetric MDS combined with the CRR diagram allows us to visually understand the resistance and cross-resistance status of each antimicrobial agent as a 2-dimensional map, as well as to understand the trends and characteristics of the data by means of quantitative values.

Background: We investigated the extent of growth of microorganisms with simultaneous administration of lipid emulsions with infusions for Total Parenteral Nutrition (TPN), assuming that the lipid emulsions contaminated with microorganisms are stagnant in a closed-type infusion device. We also investigated if bacterial growth can be prevented in the infusion device by flushing the inside of the infusion device with saline solution after the administration of lipid emulsion from the side tube in vitro setting. Methods: We made a preparation by adding Escherichia coli to the lipid emulsion and started the infusion simultaneously with the infusion solution for TPN and lipid emulsion with the piggyback method. Immediately after the completion of lipid emulsion infusion, we conducted flushing with saline solution. The volume of saline solution was none, 5, 10, or 20 mL at a flow rate of 1 mL/s. Infusion solution that was stagnant in the infusion device was collected immediately before completing the lipid emulsion infusion and 20 h after flushing, i.e., 24 h after starting the infusion for TPN, and the number of viable bacteria was determined. Results: The number of viable E. coli increased in the infusion device of all three species used in this experiment 24 h after starting the lipid emulsion infusion without flushing. We found that bacterial growth could be prevented through flushing with saline solution after the completion of lipid emulsion infusion and flushing out the stagnant infusion solution in the closed-type infusion device. Conclusions: We found that if E. coli was present in the closed-type infusion device, it would multiply. We also found that the number of viable bacteria varied according to the variety and internal structure of the closed-type infusion device as well as the liquid volume used for flushing, although flushing can prevent the growth of microorganisms. Proper management and manipulation of infusion is required to prevent infection.

BackgroundThe use of enteral nutrients plays a highly important role in accurate nutrition management, but limited information is currently available on the cautionary points of semi-solid enteral nutrients.AimIn this study, we examined whether the pharmacokinetic profiles of sodium valproate (SVA), levetiracetam (LEV), and carbamazepine (CBZ) are affected by altering the dosing time of RACOL®-NF Semi Solid for Enteral Use (RASS), a prescribed semi-solid formula. We also investigated whether the pharmacokinetic interaction observed in this study can be avoided by staggered dosing of the chemical drug and semi-solid enteral nutrient.MethodsThe plasma concentration of SVA, LEV and CBZ after oral administration was measured by LC-MS/MS method.ResultsThere was no difference in pharmacokinetic characteristics of SVA and LEV when the dosing time of RASS was altered. On the other hand, the plasma concentration of CBZ after oral administration at all sampling points decreased with the extension of the dosing time of RASS, which was consistent with the Cmaxand AUC. However, no significant difference was observed in the pharmacokinetic profiles or parameters of CBZ between the short-term and long-term RASS dosing groups by prolonging the administered interval of CBZ and RASS for 2 hr.ConclusionWe concluded that the pharmacokinetic profiles of CBZ, but not SVA and LEV, after its oral administration are affected by the dosing time of RASS, but staggered administration of CBZ and RASS prevented their interaction.

WHAT IS KNOWN AND OBJECTIVE Though most medical institutions calculate antimicrobial susceptibility and resistance rates of microbes isolated at their own facility as part of their efforts to promote the proper use of antibiotics, very few, if any, regularly monitor cross-resistance rates between antimicrobial agents. The authors have devised a tool in the form of a cross-resistance rate correlation diagram (CRR diagram) that allows easy identification of increases or decreases in, or changes in the pattern of, antimicrobial cross-resistance. The objective was to perform an analysis by CRR diagrams of the effect of relocation to a newly built facility on antimicrobial resistance and cross-resistance rates at a medical facility. METHODS The Sakai City Medical Center relocated in July 2015 to a newly built facility located in a different primary medical care zone 3.5 km away. Based on the drug susceptibility test data compiled at the Sakai City Medical Center, resistance and cross-resistance rates of Pseudomonas aeruginosa before and after the relocation of the hospital facility were calculated, and the rates were assessed using CRR diagrams. RESULTS AND DISCUSSION It was possible to confirm the effect of hospital relocation on antibiotic susceptibility of P aeruginosa in terms of changes in resistance and cross-resistance rates. The effect of the facility's relocation on cross-resistance rates was particularly notable with respect to β-lactam antibiotics: cross-resistance rates among β-lactams decreased substantially, represented as a large wedge-shaped change towards the origin on the CRR diagram. Rates of cross-resistance between classes of antibiotics with a different mechanism of antibiotic action changed little. WHAT IS NEW AND CONCLUSION Including cross-resistance rates in the routine monitoring of resistance and susceptibility rates practiced by a medical institution can provide a comprehensive insight into the dynamics of bacterial flora in the facility. CRR diagrams, which allow visualization of the status and changes in cross-resistance, not only provide a new perspective for clinicians, but they also contribute to the proper use of antibiotics and serve as a tool in the education of healthcare professionals and students about antibiotic resistance.

BackgroundTo support effective antibiotic selection in empirical treatments, infection control interventions, and antimicrobial resistance containment strategies, many medical institutions collect antimicrobial susceptibility test data conducted at their facilities to prepare cumulative antibiograms.AimTo evaluate how the setpoints of duplicate isolate removal period and data collection period affect the calculated susceptibility rates in antibiograms.MethodsThe Sakai City Medical Center is a regional core hospital for tertiary emergency medical care with 480 beds for general clinical care. In this study, all the Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae isolates collected at the Sakai City Medical Center Clinical Laboratory between July 2013 and December 2018 were subjected to antimicrobial susceptibility tests and the resulting data was analyzed.FindingsThe longer the duplicate isolate removal period, the fewer the isolates are available for every bacterial species. Differences in the length of the duplicate isolate removal period affected P. aeruginosa susceptibility rates to β-lactam antibiotics by up to 10.8%. The setpoint of the data collection period affected the antimicrobial susceptibility rates by up to 7.3%. We found that a significant change in susceptibility could be missed depending on the setting of the data collection period, in preparing antibiogram of β-lactam antibiotics for P. aeruginosa.ConclusionsWhen referring to antibiograms, medical professionals involved in infectious disease treatment should be aware that the parameter values, such as the duplicate isolate removal period and the data collection period, affect P. aeruginosa susceptibility rates especially to β-lactam antibiotics. And antibiogram should be updated within the shortest time period that is practically possible, taking into account restrictions such as numbers of specimen.

The use of semi-solid enteral nutrients plays an extremely important role in accurate nutrition management. In the present study, we compared the pharmacokinetic profile of orally administered carbamazepine (CBZ) in rats treated with liquid RACOL®, semi-solid RACOL®, and HINE E-gel®, which are enteral nutrients marketed in Japan. Since liquid and semi-solid formulations are both marketed in Japan for RACOL®, liquid RACOL® was orally administered to control rats. The serum concentration of CBZ at each sampling point was lower in the semi-solid RACOL®-treated group than in the liquid RACOL®-treated group. No significant differences were observed in the pharmacokinetic behavior of CBZ between the semi-solid RACOL®-treated and HINE E-gel®-treated groups. Regarding pharmacokinetic parameters, the impact of the area under the curve (AUC0→5h) was the liquid RACOL® group > the semi-solid RACOL® group ≈ the HINE E-gel® group. Therefore, we concluded that serum concentrations of CBZ were lower when concurrently treating with semi-solid enteral nutrients than when simultaneously processing liquid enteral nutrients.

Doxorubicin (DOX) is a highly potent anti-neoplastic agent widely used in clinical practice, but its dosage and duration of administration are strictly limited due to dose-related organ damage. In the present study, we examined whether theanine, an amino acid derivative found in green tea leaves, can protect against DOX-induced acute nephrotoxicity in rats. Decreases in the creatinine clearance by DOX administration were attenuated by concurrent treatment with theanine, which was consistent with the change in histological renal images assessed by microscopic examination. Theanine had no effect on the distribution of DOX to the kidney. The production of lipid peroxide in the kidney after DOX administration was suppressed by concurrent treatment with theanine. Reduced glutathione content, but not superoxide dismutase activity, was decreased following DOX administration, whereas this change was suppressed when theanine was given in combination with DOX. These results suggest that theanine prevents DOX-induced acute nephrotoxicity through its antioxidant properties.

Background Menthol is widely used as a constituent of functional foods and chemical drugs. In the present study, we investigated changes in the expression of cytochrome P450 isoform CYP3A4mRNA after treating human hepatocellular carcinoma HepG2 cells with menthol. We also examined the effects of pretreatment with menthol on the cytotoxic activity of paclitaxel (PAC) and vincristine (VIN), which are substrates of CYP3A4, in the cells. Methods HepG2 cells were maintained in Dulbecco’s Modified Eagle’s Medium. Expression of CYP3A4 was examined by the real-time polymerase chain reaction. Survival rate of HepG2 cells was evaluated by the MTT assay. Results The gene expression level of CYP3A4 in HepG2 cells was significantly reduced by treatment with menthol for 1 day. The viability of HepG2 cells was not affected by treatment with menthol alone once a day for two consecutive days. The degree of reduction in cell viability by PAC or VIN in HepG2 cells was significantly increased by menthol treatment for 24 h prior to exposure to these anti-cancer drugs. Conclusions These results demonstrate that menthol enhanced the anti-tumor effects of PAC and VIN through the downregulation of CYP3A4 in HepG2 cells without exerting cytotoxic activity.

1. We investigated the change in the pharmacokinetic profile of tolbutamide (TB), a substrate for CYP2C6/11, 4 days after single administration of 5-fluorouracil (5-FU), and the hepatic gene expression and activity of CYP2C6/11 were also examined in 5-FU-pretreated rats. 2. Regarding the pharmacokinetic parameters of the 5-FU group, the area under the curve (AUC) was significantly increased, and correspondingly, the elimination rate constant at the terminal phase (ke) was significantly decreased without significant change in the volume of distribution at the steady state (Vdss). 3. The metabolic production of 4-hydroxylated TB in hepatic microsomes was significantly reduced by the administration of 5-FU. 4. The expression level of mRNAs for hepatic CYP2C6 and CYP2C11 was significantly lower than in the control group when the rats were pretreated with 5-FU. 5. These results demonstrated that the pharmacokinetic profile of TB was altered by the treatment with 5-FU through a metabolic process, which may be responsible for the decreased CYP2C6/11 expression at mRNA levels.

Peripheral parenteral nutrition (PPN) solutions contain amino acids, glucose, and electrolytes, with or without some water soluble vitamins. Peripheral venous catheters are one of the causes of catheter related blood stream infection (CRBSI), which requires infection control. In Japan, PPN solutions have rarely been prepared under aseptic conditions. However, in recent years, the necessity of adding vitamins to infusions has been reported. Therefore, we investigated the effects of water soluble vitamins on growth of microorganisms in PPN solutions. AMINOFLUID® (AF), BFLUID® (BF), PARESAFE® (PS) and PAREPLUS® (PP) PPN solutions were used. Water soluble vitamins contained in PP were also used. Causative microorganisms of CRBSI were used. Staphylococcus epidermidis decreased after 24 hours or 48 hours in all solutions. On the other hand, Escherichia coli, Serratia marcescens, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans increased, especially in PP. When each water soluble vitamin was added to BF and PS, growth of S. aureus was greater in solutions that contained nicotinamide than in solutions that contained other vitamins. As for C. albicans, they grew in all test solutions. C. albicans grew especially well in solutions that contained biotin. When commercial amino acids and glucose solutions with electrolytes are administered, in particular those containing multivitamins or water soluble vitamins, efforts to control infection must be taken to prevent proliferation of microorganisms.

Objective: A palliative care knowledge survey was conducted involving pharmacy students to examine their perceived usefulness and the educational effect of clinical training in hospitals. Methods: A questionnaire sheet was distributed to fifth-year pharmacy students before and after clinical training. The questionnaire consisted of questions to clarify the details of palliative care-related training in hospitals and students’ knowledge of such care. The respondents were divided into 2 groups: those who participated in palliative care team (PCT) rounds (group A: 57) and those who did not (group B: 57). Results: The mean total correct answer rate markedly increased after training in group A, from 37.9 to 47.1% (P < .01). Such an increase was also observed in the domains of philosophy and pain in this group ( P < .01). In contrast, group B did not show differences in the mean correct answer rate between before and after training; there was no significant increase in the rate in any domain. Conclusion: Pharmacy students’ knowledge was enhanced by participating in the PCT, confirming the usefulness of such participation during training as part of palliative care education.

Objective The use of enteral nutrients plays an extremely important role in accurate nutrition management. Sodium alginate (SA) is frequently used for the semi-solidification of enteral nutrients. In the present study, we investigated whether the pharmacokinetic profile of orally administered carbamazepine (CBZ) is altered by a treatment with SA immediately before and after dosing of the drug. Furthermore, the adsorption effects of SA on CBZ were examined using an in vitro analysis. Method SA was orally administered to rats just before and immediately after CBZ dosing. The CBZ concentration profile following its oral administration was analyzed by a non-compartmental method. The adsorption of CBZ onto SA was evaluated after centrifugation using an ultrafiltration device. Findings The serum concentration of orally administered CBZ at each sampling point was reduced by the treatment with SA, and the extent of the decrease observed in the concentration of CBZ was larger when SA was ingested immediately after administration of the drug, which was consistent with the alteration observed in the value of the area under the curve (AUC). No significant differences were noted in the elimination rate at the terminal phase (ke) among the groups. In the in vitro assay, CBZ was adsorbed by SA in the solution used to reflect fluid in the intestinal tract. Conclusions The pharmacological efficacies of CBZ might be reduced by SA through the pharmacokinetic interactions, and that the careful attention should be paid to the timing of administration of CBZ and semi-solid enteral nutrients.

Background: The Guidelines for Parenteral and Enteral Nutrition in Japan state that parenteral fat emulsion can be infused through a secondary administration set. We tested the compatibility of fat emulsion with antibiotics in piggyback infusions in terms of changes in the size distribution of fat particles. Methods: Test mixtures of 5% glucose solution, fat emulsion, and 25 antibiotic agents were prepared in the ratio appropriate for piggyback infusion (33: 10: 40) and analyzed serially for the number of fine particles by size using a light-shielded automatic fine particle counter. Results: No marked changes were observed in the 12 β-lactam antibacterial drugs, clindamycin phosphate, teicoplanin, trimethoprim/sulfamethoxazole, and micafungin sodium even at 24 h after preparation. The particle size in the mixture containing vancomycin hydrochloride, levofloxacin hydrate, metronidazole, and fluconazole gradually increased after preparation. The particle size in the mixture containing gentamicin sulfate, arbekacin sulfate, minocycline hydrochloride, ciprofloxacin, and fosfomycin sodium changed significantly after preparation. Conclusions: The changes in the particle size observed with some drugs suggest that they may cause changes in the lipid particle size during administration and, therefore, those antibiotics agents should not be administered concurrently with fat emulsion.

Objective The management of nutrition using semisolid enteral nutrients is considered useful for avoiding the adverse effects associated with liquid enteral nutrients. In the present study, we used an in vitro analysis to investigate whether carbamazepine (CBZ) is adsorbed by the fibers included in semisolid enteral nutrients. The effects of these fibers on the pharmacokinetic profile of CBZ following its oral administration were also examined in rats. Methods The adsorption of CBZ onto fibers was examined by absorbance monitoring of the filtrate after centrifugation using an ultrafiltration device. Viscosities of each solution were measured by rotational viscosimeter. The CBZ concentration profile after its oral administration (50 mg/kg) was analyzed by a noncompartmental method. Results In the two solutions used to reflect gastric juice and fluid in the intestinal tract, CBZ was more strongly adsorbed by water-soluble fibers (guar gum and xanthan gum) than by insoluble fibers (dextrin hydrate). The adsorption of CBZ also was observed even if the concentrations of guar gum and xanthan gum were reduced to such an extent that viscosity was 0 Pa･s. The pharmacokinetic examination of orally administered CBZ revealed that the area under the curve was significantly lower in the guar gum and xanthan gum groups than in the control group. Conclusion CBZ was adsorbed by fibers used for the semisolidification of enteral nutrients, which may be partially responsible for the alterations observed in the pharmacokinetic profile of CBZ.