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.

Collaboration with an infection control team promoted appropriate antibiotic use for third molar extraction at a Japanese hospital.

Oral antibiotic therapy is routinely administered when a third molar (M3) is extracted to prevent infectious complications after surgery. Oral third-generation cephalosporins are frequently used after M3 extraction in Japan but at the expense of an increased risk of antimicrobial resistance. Therefore, the infection control team (ICT) at our institution recommended a reduction in use of these agents after M3 extraction. In this study, we compared the types of antibiotic agents prescribed for patients undergoing M3 extraction before and after this recommendation. We investigated the relationship between type of antibiotic used and the likelihood of infectious complications as well as cost savings in patients who underwent M3 extraction in the 6 months before and after the ICT recommendation in July 2018. There was a marked reduction in use of oral third-generation cephalosporins after M3 extraction (P < 0.0001) and increased use of oral penicillins and first-generation cephalosporins after the ICT recommendation. Moreover, surgical site infection (SSIs) were significantly less common after the ICT recommendation (P = 0.0099); however, the SSI rate was higher in patients who received a third-generation cephalosporin than in those who received penicillin (8.8% vs 0.5%). There was also a significant saving in per-patient antibiotic costs after the ICT recommendation (269.5 ± 282.0 JPY vs 454.7 ± 376.6 JPY; P < 0.0001). These findings suggest that collaboration with an ICT promotes appropriate antibiotic use, decreases the risk of an SSI, and improves the cost-benefit ratio in patients undergoing M3 extraction.

Influence of UGT1A1 polymorphism on etoposide plus platinum-induced neutropenia in Japanese patients with small-cell lung cancer.

BACKGROUND: The association between UGT1A1 polymorphism and etoposide-induced toxicities is still not clear. The aim of this study was to assess the association between uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphism and severe hematologic toxicities in Japanese patients receiving etoposide plus platinum chemotherapy for small-cell lung cancer. METHODS: This retrospective analysis included patients with small-cell lung cancer who had received their first-line chemotherapy with etoposide plus cisplatin or carboplatin, between October 2008 and April 2018, at the University of Fukui Hospital. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia as well as thrombocytopenia was evaluated. RESULTS: A total of 55 patients were enrolled. The incidence of grade 4 neutropenia during the first cycle of etoposide-based chemotherapy was higher in patients with homozygous (hmz) polymorphisms for UGT1A1*28 and *6 (*28/*28, *6/*6, and *6/*28) than in patients with wild-type (wt) (*1/*1) and heterozygous (htz) (*1/*28 and *1/*6) polymorphisms (88% vs 43% P = 0.03). The incidence of febrile neutropenia and grade 4 thrombocytopenia, however, was not significantly different. Multivariate analysis suggested that grade 4 neutropenia associated significantly with an hmz UGT1A1 genotype [odds ratio (OR) 11.3; P = 0.04] and administration of granulocyte colony-stimulating factor (G-CSF) before the neutrophil counts dropped to < 500 cells/µL (OR; P = 0.01). CONCLUSIONS: UGT1A1*28 and UGT1A1*6 mutations might be regarded as predictors for etoposide-induced grade 4 neutropenia.

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.

Pharmacoethnicity of docetaxel-induced severe neutropenia: integrated analysis of published phase II and III trials.

BACKGROUND: Ethnic differences in drug susceptibility and toxicity are a major concern, not only in drug development but also in the clinical setting. We review the toxicity profiles of docetaxel according to dose and ethnicity. METHODS: We analyzed phase II and III clinical trials that included a once-every-3-weeks single-agent docetaxel arm. Logistic regression analysis was applied to identify the significant variables affecting the reported incidence of docetaxel-induced severe neutropenia. RESULTS: Multivariate logistic regression analysis identified studies conducted in Asia [odds ratio (OR) 19.0; 95% confidence interval (95% CI) 3.64-99.0] and docetaxel dose (OR 1.08; 95% CI 1.03-1.13) as independent variables for the incidence of grade 3/4 neutropenia. CONCLUSIONS: There is a significant difference in the incidence of docetaxel-induced severe neutropenia between Asian and non-Asian clinical studies. Physicians and pharmacists should consider ethnic diversity in docetaxel toxicity when interpreting the results of clinical trials.

Predictors of response of patients with solid tumors to granulocyte colony-stimulating factor.

BACKGROUND: Granulocyte colony-stimulating factor administration is an important component of supportive therapy in chemotherapy-induced leukopenia. Although patient response to granulocyte colony-stimulating factor administration is known to vary, the factors responsible for poor response have not been identified. OBJECTIVE: To identify the predictors of the responses of patients with solid tumors to granulocyte colony-stimulating factor. SETTING: A 600-bed university hospital offering secondary and tertiary care in Japan. METHODS: This retrospective cohort study examined the response of 181 patients with solid tumors who were administered prophylactic granulocyte colony-stimulating factor for the first time after they developed severe grade 3/4 leukopenia (white blood cell count <2,000 × 10(-9)/L) because of adjuvant or neoadjuvant chemotherapy. The granulocyte colony-stimulating factor response was defined as the length of the leukocyte recovery period, which was assessed as the period within which the normal white blood cell count (white blood cell count >3,000 × 10(-9)/L) is reached after the first dosage of granulocyte colony-stimulating factor. After classification of the patients as either poor or normal granulocyte colony-stimulating factor responders according to the confidence interval of the recovery period, their characteristics were compared. MAIN OUTCOME MEASURE: The time for recovery to normal white blood cell count was 2-7 days (90 % confidence interval), and the cutoff value for differentiating poor responders (n = 14) from normal responders (n = 167) was 8 days. Univariate analysis identified previous radiotherapy, number of chemotherapy courses, high granulocyte colony-stimulating factor dosage, and hypoalbuminemia to be significantly associated with granulocyte colony-stimulating factor response. Multivariate analysis identified undergoing four or more chemotherapy courses (odds ratio = 5.09; 95 % confidence interval, 1.14-22.71) and heart failure (odds ratio = 5.96; 95 % confidence interval, 1.09-32.57) to be significantly associated with poor granulocyte colony-stimulating factor response. CONCLUSIONS: Undergoing four or more chemotherapy courses and heart failure are independent risk factors for poor response to granulocyte colony-stimulating factor. These findings may help prevent the complications of leukopenia during chemotherapy and highlight the need to develop better strategies for preventing and treating infectious disease in patients undergoing granulocyte colony-stimulating factor administration.

Evaluation of potential interaction between vinorelbine and clarithromycin.

BACKGROUND: Myelotoxicity, a major toxicity of vinorelbine. may be related to the degree of one's exposure to vinorelbine. In theory, clarithromycin has the potential to alter vinorelbine's pharmacokinetics by inhibiting CYP3A and/or P-glycoprotein; this may result in massive exposure to vinorelbine and severe toxicity. To date, macrolide-vinorelbine drug interactions have not been reported. OBJECTIVE: To estimate the clinical risk of a interaction between vinorelbine and clarithromycin. METHODS: In a retrospective cohort study, we searched computerized medical records of patients who had been administered vinorelbine in the University of Fukui Hospital. The study cohort was defined as all patients with non-small-cell lung cancer who received vinorelbine between May 30, 2003, and January 31, 2008. The treatment courses were classified according to whether or not clarithromycin was concomitantly administered with vinorelbine. Nadir neutrophil counts were recorded as the major outcomes. Vinorelbine-clarithromycin interaction was defined as a significant increase in the risk of severe neutropenia when the 2 drugs were administered concomitantly. RESULTS: A total of 12 (63.2%) and 11 (27.5%) episodes of grade 3/4 neutropenia occurred among the patients who were and were not administered clarithromycin, respectively. The incidence of grade 4 neutropenia was higher in the group administered clarithromycin than in those who did not receive it (31.6% vs 2.5%; p = 0.0033). Vinorelbine dose, concomitant clarithromycin administration, and female sex were significantly correlated with severe neutropenia, with unadjusted odds ratios of 0.07 (95% CI 0.01 to 0.59), 4.52 (95% CI 1.41 to 14.45), and 4.55 (95% CI 1.39 to 14.29), respectively. CONCLUSIONS: Compared with patients who are administered vinorelbine alone, patients who are administered clarithromycin during chemotherapy with vinorelbine are at a higher risk for severe neutropenia. Physicians should educate their patients about this interaction. If possible, clarithromycin administration should be avoided in patients who will undergo chemotherapy with vinorelbine in the near future. However, further prospective pharmacokinetic studies are required to confirm this interaction.

Variability in teicoplanin protein binding and its prediction using serum albumin concentrations.

The impact of lower serum albumin levels on teicoplanin pharmacokinetics has not been previously determined. The authors assessed the relationship between total and free concentrations of teicoplanin in serum samples obtained from patients receiving teicoplanin therapy for Gram-positive bacterial infections. In addition, the authors determined the contribution of serum albumin concentrations to the unbound fraction of teicoplanin. One hundred ninety-eight serum samples were obtained from 65 patients undergoing routine therapeutic drug monitoring of teicoplanin. Free serum teicoplanin was separated by ultrafiltration, and total and free serum concentrations of teicoplanin were determined by a fluorescence polarization immunoassay. Regression analysis was then performed to build a prediction model for the free serum teicoplanin concentration from the total serum teicoplanin concentration and the serum albumin level using the first 132 samples. The predictive performance of this model was then tested using the next 66 samples. Free serum teicoplanin concentrations (Cf) (mug/mL) were predicted using a simple model constructed using total serum teicoplanin (Ct) (mug/mL) and albumin concentrations (ALB) (g/dL): Cf = Ct/(1 + 1.78 * ALB). This model could estimate free serum teicoplanin concentrations with a small bias and an acceptable error. The measured free level of teicoplanin will lie between 0.63 and 1.38 times the predicted concentration in 95% of cases. Serum albumin level plays a major role in the variability of the fraction unbound of teicoplanin. This model can reliably estimate free serum teicoplanin concentrations more easily than by using direct measurements.