A longitudinal study of Candida bloodstream infections in a Japanese university hospital: species distribution, drug susceptibility, clinical features, and mortality predictors.

We aimed to detect possible changes in Candida species distribution over time and to know the antifungal susceptibility profile of isolates obtained from patients with bloodstream infection (BSI) due to this pathogen. Risk factors associated with 30-day mortality were also assessed. We conducted a retrospective cohort study of patients diagnosed with Candida BSI at a Japanese university hospital from 2013 to 2021. The change in the distribution pattern of the Candida spp. isolated was examined by considering three successive sub-periods of 3 years each. Risk factors for 30-day mortality were determined using Cox regression analysis. In the entire study period, Candida albicans was the most frequent species (46.7%), followed by Candida glabrata (21.5%) and Candida parapsilosis (18.7%). There was no change in Candida species distribution comparing the three sub-periods analyzed. All isolates were susceptible to micafungin, and most were susceptible to fluconazole, except for C. glabrata. No isolates were resistant to amphotericin B or voriconazole. The overall 30-day mortality was 40.2%. Univariate analysis revealed an association between 30-day mortality and central venous catheter (CVC) removal at any time, high Pitt bacteremia score (PBS), and high Charlson comorbidity index (CCI). Multivariate Cox analysis found that high PBS was the only independent predictor of 30-day mortality; subsequent multivariate Cox regression demonstrated that early CVC removal significantly reduced 30-day mortality. Candida species distribution and antifungal susceptibility profile in our hospital remained similar from 2013 to 2021. Early CVC removal may improve candidemia outcomes.

Association of methicillin resistance with mortality of hospital-acquired Staphylococcus aureus bacteremia.

OBJECTIVE: Methicillin-resistant (MR) Staphylococcus aureus bacteremia (SAB) is associated with higher mortality rates than methicillin-susceptible (MS) SAB. This study assessed potential predictors of mortality and evaluated the association of methicillin resistance with mortality in patients with SAB. METHODS: We conducted a retrospective cohort study in patients with hospital-acquired SAB, from 2009 to 2018. Clinical features of patients with MR-SAB were compared with those of patients with MS-SAB and predictors of 30-day mortality were determined using Cox regression analysis. RESULTS: Among 162 patients, 56.8% had MR-SAB. Overall 30-day mortality was 19.1%; MR-SAB had higher mortality (25.0%) than MS-SAB (11.4%). Univariate analysis highlighted long-term hospitalization, prior antibiotics use, and delayed initiation of appropriate antibiotics as risk factors. Cox regression analysis showed that respiratory tract source, Pitt bacteremia score, Charlson comorbidity index, and appropriate antibiotic therapy within 24 hours were independently and significantly associated with 30-day mortality outcome. CONCLUSIONS: Methicillin resistance was not an independent risk factor for mortality in patients with SAB. Early, appropriate antibiotic treatment is an important prognostic factor.

Population pharmacokinetic model development and exposure-response analysis of vincristine in patients with malignant lymphoma.

PURPOSE: Vincristine (VCR) is a key drug for treating various malignancies. However, few data are available on the pharmacokinetics of VCR, especially in adult patients. The objective of this study was to clarify the population pharmacokinetics and exposure-response relationships of VCR in adult malignant lymphoma patients. METHODS: Blood samples were collected from patients who were administered R-CHOP-like regimens, and the VCR plasma concentration was determined using liquid chromatography-mass spectrometry. Using NONMEM software, population pharmacokinetic parameters were estimated, and covariates were evaluated. The relationships between the individual parameters and adverse events or therapeutic effects were also investigated. RESULTS: Plasma concentrations were measured in 30 patients. In the final population pharmacokinetics model, body surface area and age were incorporated into clearance as significant covariates. The inter-individual variations in clearance and volume of distribution in the central and third compartments were 17.0, 26.6, and 66.3%, respectively, and the residual variability in the plasma concentration was 23.8%. Although the variability observed in the volume of distribution was large, good predictability was obtained in the individual estimation. The severity of anemia and peripheral neuropathy was correlated with clearance and peak concentration, respectively (adjusted P = 0.040 and 0.024, respectively). In diffuse large B cell lymphoma patients, those with higher area under the curve and dose experienced longer progression-free survival (P = 0.023 and 0.013, respectively). CONCLUSION: The population pharmacokinetics of VCR were evaluated in adult malignant lymphoma patients. VCR pharmacokinetic data could explain in part the adverse events and prognosis of these patients.

The Inhibitory Effect of Ciprofloxacin on the ß-Glucuronidase-mediated Deconjugation of the Irinotecan Metabolite SN-38-G.

The enterohepatic recycling of a drug consists of its biliary excretion and intestinal reabsorption, which is sometimes accompanied by hepatic conjugation and intestinal deconjugation reactions. ß-Glucuronidase, an intestinal bacteria-produced enzyme, can break the bond between a biliary excreted drug and glucuronic acid. Antibiotics such as ciprofloxacin can reduce the enterohepatic recycling of glucuronide-conjugated drugs. In this study, we established an in vitro system to evaluate the ß-glucuronidase-mediated deconjugation of the irinotecan metabolite SN-38-G to its active SN-38 form and the effect of ciprofloxacin thereon. SN-38 formation increased in a time-dependent manner from 5 to 30 min. in the presence of ß-glucuronidase. Ciprofloxacin and phenolphthalein-ß-D-glucuronide (PhePG), a typical ß-glucuronidase substrate, significantly decreased SN-38-G deconjugation and, hence SN-38 formation. Similarly, the antibiotics enoxacin and gatifloxacin significantly inhibited the conversion of SN-38-G to SN-38, which was not observed for levofloxacin, streptomycin, ampicillin and amoxicillin/clavulanate. Ciprofloxacin showed a dose-dependent inhibitory effect on the ß-glucuronidase-mediated conversion of SN-38-G to SN-38 with a half-maximal inhibitory concentration (IC50 ) value of 83.8 µM. PhePG and ciprofloxacin afforded the inhibition in a competitive and non-competitive manner, respectively. These findings suggest that the reduction in the serum SN-38 concentration following co-administration of ciprofloxacin during irinotecan treatment is due, at least partly, to the decreased enterohepatic circulation of SN-38 through the non-competitive inhibition of intestinal ß-glucuronidase-mediated SN-38-G deconjugation.

Clinical effect of a multidisciplinary team approach to the initial treatment of patients with hospital-acquired bloodstream infections at a Japanese university hospital.

BACKGROUND: Hospital-acquired bloodstream infections (BSIs) are significant causes of mortality, and strategies to improve outcomes are needed. We aimed to evaluate the clinical efficacy of a multidisciplinary infection control team (ICT) approach to the initial treatment of patients with hospital-acquired BSI. METHODS: A before-after quasiexperimental study of patients with hospital-acquired BSI was performed in a Japanese university hospital. The ICT provided immediate recommendations to the attending physician about appropriate antimicrobial therapy and management after reviewing blood cultures, Gram's stain, final organism, and antimicrobial susceptibility results. RESULTS: The sample included 469 patients with hospital-acquired BSI (n = 210, preintervention group; n = 259, postintervention group). There were no significant differences between the groups in background or microbiologic characteristics. The 30-day mortality was significantly lower and significantly more patients received appropriate antimicrobial therapy in the postintervention group (22.9% vs 14.3%; P = .02 and 86.5% vs 69.0%; P < .001, respectively). Multivariate analysis confirmed that the ICT intervention was significantly associated with appropriate antimicrobial therapy (odds ratio, 2.22; 95% confidence interval, 1.27-3.89) and 30-day mortality (odds ratio, 0.49; 95% confidence interval, 0.25-0.95). CONCLUSIONS: A timely multidisciplinary team approach decreases the delay of appropriate antimicrobial treatment and may improve HABSI patient outcomes.

Variations in the Blood Phenytoin Levels during Long-Term Combined Treatment with S-1 and Phenytoin.

Although combination therapy with the oral fluoropyrimidine anticancer drug S-1 and the anticonvulsant phenytoin (PHT) is known to increase blood levels of PHT and the risk of intoxication, reports on long-term monitoring of blood levels of PHT during combined S-1 and PHT treatment and a thorough understanding of their interaction are lacking. This report aims to describe interactive effects of S-1 and PHT through long-term therapeutic drug monitoring of PHT. A 72-year-old male had been prescribed oral PHT (130 mg/day) for over 20 years and started receiving S-1 therapy (80 mg/day for 4 weeks, followed by a 2-week rest) as postoperative adjuvant chemotherapy for gastric cancer. The blood PHT level was continuously monitored. Prior to receiving S-1, the patient's blood PHT concentration was 6.0 µg/ml, but it increased during S-1 therapy, reaching 22.9 µg/ml on day 84 (during a rest period of second cycle S-1 therapy). After reducing his PHT dosage to 100 mg/day, it never reached toxic levels (4.0-10.4 µg/ml). It was difficult to keep blood PHT concentrations constant because of the time lag between the period of combined use of S-1 and PHT and the timing of manifestation and disappearance of the drug interaction. The DIPS probability scale indicated a highly probable interaction between S-1 and PHT. We conclude that, when S-1 and PHT are used concurrently, occurrence and disappearance time of their interaction need to be predicted to maintain an effective and safe PHT concentration.

Mechanism responsible for the decreased hepatic NADPH generation rate in rats with bilateral ureter ligation-induced renal failure.

We previously reported that a decrease in hepatic NADPH generation results in reduced hepatic first-pass clearance of propranolol in rats with bilateral ureteral ligation (BUL)-induced renal failure. The aim of the present study was to evaluate the mechanisms responsible for the reduced NADPH generation in the supernatant of liver homogenates (SUP) obtained from rats with BUL. The NADPH generation in the SUP in the presence of NADP(+) was decreased in BUL rats as compared with control rats. After the addition of glucose-6-phosphate or 6-phosphogluconic acid, the increase in NADPH in the SUP of BUL rats was similar to that in control rats. The NADPH generation in the SUP after the addition of the ultrafiltrate of BUL rat SUP was smaller than that after the addition of the ultrafiltrate of control rat SUP. These findings suggest that the enzymatic activities in the pentose phosphate pathway were not decreased significantly in BUL rats, and that the decrease in the generation of NADPH in BUL rats was mainly caused by the decreased concentration of endogenous substrate(s) and/or the increased concentration of endogenous inhibitor(s) for the pentose phosphate pathway.

Hardness and Young's modulus of transparent dentin associated with aging and carious disease.

This study investigated the changes in hardness and Young's modulus of the transparent layer of dentin associated with aging and the carious process. Eighteen extracted human molars with or without coronal caries were used in this study. The normal teeth were divided into two groups by age, and the carious teeth were divided into two groups of active or arrested caries. After polishing the specimens parallel to the long axis of the tooth, both hardness and Young's modulus were measured using a nanoindentation tester. The hardness and Young's modulus of the transparent layer in aged dentin were higher than the other portions of aged dentin. The transparent layer under carious lesions had a significantly lower hardness than the underlying normal dentin, whereas its Young's modulus was not significantly reduced. The hardness and Young's modulus of the transparent layer in active carious lesions were lower than those in arrested carious lesions.

Intestinal absorption and hepatic extraction of propranolol and metoprolol in rats with bilateral ureteral ligation.

To investigate the mechanism responsible for the increased bioavailability of propranolol in bilateral ureter-ligated (BUL) rats, the intestinal absorption and hepatic extraction of propranolol and metoprolol were evaluated. The initial absorption rate of these drugs after intra-intestinal administration was only slightly increased in the BUL rats, whereas the blood drug concentration in these rats was higher than that in control rats. The blood propranolol and metoprolol concentrations during intra-portal infusion in the BUL rat were significantly higher than that in the control rat. In the presence of NADPH, the intrinsic metabolic activity of metoprolol in hepatic microsomes was not altered by BUL. On the other hand, the NADPH generation rate in the hepatic cytosol in the BUL group was lower than that in the control group. These results indicate that the absorption rate-dependent decrease in hepatic first-pass clearance of propranolol and metoprolol due to saturation kinetics is marginal, and that the hepatic metabolic activity and extraction of the drugs is significantly decreased in BUL rats probably due to the reduced NADPH generation rate in the liver.

Histologic evaluation of adhesive restorations on dentin caries in rat molar teeth.

OBJECTIVE: The aim of this study was to evaluate the progress of dentin caries under resin composite and glass-ionomer cement restorations in vivo. METHOD AND MATERIALS: Sixteen rats were subjected to oral inoculation of the bacterial strain, Streptococcus mutans, and experimental dental caries was induced in the rats' molars. The dental caries induced in rat molars was sealed with resin composite or glass-ionomer cement without removal of the caries; the depth and width of bacterial penetration in the lesion were measured from histopathologically stained sections. Inflammatory cell infiltrations within the pulp were also examined. RESULTS: Both bacterial penetration into dentin and caries spread were significantly reduced by sealing with glass-ionomer cement or resin composite. No significant differences in bacterial penetration and caries spread were seen between the sealing materials. Regarding the pulpal reactions, moderate to severe inflammatory cell infiltration was observed even in the sealed teeth. CONCLUSION: The caries lesions could not be completely arrested by sealing alone, although their progress was slowed from an active to a chronic status.