Evaluation of predictors of third-generation cephalosporin non-susceptibility and factors affecting recurrence or death in bacteremia caused by Citrobacter freundii complex, Enterobacter cloacae complex, and Klebsiella aerogenes.

Factors involved in the susceptibility of third-generation cephalosporins (3GCs) to bacteremia caused by Citrobacter freundii complex, Enterobacter cloacae complex, and Klebsiella aerogenes were investigated based on a case-case-control design. Antimicrobial therapy administered 30 days prior to bacteremia and hospitalization within 90 days were common risk factors for the 3GC susceptible and 3GC non-susceptible groups, while hospitalization from an institution or another hospital was a specific risk factor for the 3GC non-susceptible group. We also attempted to examine the factors affecting the clinical outcome of bacteremia. Hospitalization more than 14 days before the onset of bacteremia was an independent factor indicating poor clinical outcome. In contrast, the implementation of source control was an independent predictor of successful treatment. Although a longer hospital stay before the onset of bacteremia was associated with worse clinical outcomes, implementation of source control may have contributed to improved treatment outcomes for bacteremia.

The Clinical Evaluation of Third-generation Cephalosporins As Definitive Therapy for Enterobacter spp. and Klebsiella aerogenes Bacteremia.

Objective Third-generation cephalosporins (3GCs) may be susceptible in vitro to Enterobacter spp. and Klebsiella aerogenes. However, treatment with mainly fourth-generation cephalosporins or carbapenems is currently recommended. Diversification of antimicrobial agents in therapy is required to avoid the selection pressure of resistant organisms by broad-spectrum antimicrobial agents. This study investigated the clinical efficacy of 3GC therapy for Enterobacter spp. and Klebsiella aerogenes bacteremia in a multicenter, retrospective, observational study. Methods Patients with Enterobacter spp. or Klebsiella aerogenes detected in blood cultures and treated with a susceptible antimicrobial agent were included in the study. Propensity score matching was performed to align patient background bases, and clinical outcomes between the 3GC and non-3GC groups were compared. Treatment success was defined as having no need for treatment escalation or the addition of other antimicrobial agents, no recurrence, or no death within 30 days. Results The study included 188 cases, of which 57 and 131 were included in the 3GC and non-3GC treatment groups, respectively; 53 patients in each group were matched by propensity score matching. There were no significant differences between groups in rates of switching to a susceptible antimicrobial or adding another agent, relapse within 30 days, or death within 30 days. In the 3GC group, source control was associated with favorable clinical outcomes. Conclusion Definitive 3GC therapy for susceptible Enterobacter spp. and Klebsiella aerogenes bacteremia is as clinically effective and valuable a targeted therapy as non-3GC therapy and can be implemented under conditions in which infection source control measures are in place.

[Decreased Serum Copper Concentrations by Zinc Administration in Preterm Infants with Hypozincemia Are Associated with a Lower Postmenstrual Age: A Single-center Retrospective Observational Study].

Copper is one of the essential trace elements in humans, and its deficiency causes various diseases. Zinc acetate dihydrate is administered to treat hypozincemia in preterm infants; however, zinc inhibits the gastrointestinal absorption of copper, which may cause copper deficiency. To safely treat hypozincemia in preterm infants, we retrospectively analyzed the factors reducing serum copper concentrations when zinc is administered to preterm infants with hypozincemia. Seventy preterm infants were included in the present study. Serum zinc and copper concentrations, doses, and other clinical characteristics were retrieved from electronic medical records. The administration of zinc acetate dihydrate decreased serum copper concentrations in 21 out of 70 patients. In comparisons between the two groups with and without a decrease in serum copper concentrations, significant differences were observed in postmenstrual age (34.9 and 35.9 weeks, respectively) and serum zinc concentrations (62.0 and 58.0 µg/dL, respectively) at the start of the zinc acetate dihydrate treatment. A logistic regression analysis identified postmenstrual age as a significant factor decreasing serum copper concentrations. In the ROC curve, the cut-off value for postmenstrual age for a decrease in serum copper concentrations was 34.143 weeks. The present results suggest that when zinc acetate dihydrate is administered to preterm infants with a low postmenstrual age who are at higher risk of decreased serum copper concentrations, particularly to those with a postmenstrual age <34 weeks, it is important to consider copper deficiency and periodically measure serum copper concentrations.

Administration of zinc to preterm infants with hypozincemia does not reduce serum copper concentrations in most cases: a single-center retrospective observational study.

BACKGROUND: Zinc is an essential trace element involved in various physiological functions. In Japan, zinc acetate dihydrate is administered to neonates and infants with hypozincemia. Since serum copper concentrations are reduced by the administration of zinc, we retrospectively investigated changes in serum zinc and copper concentrations in preterm infants with hypozincemia receiving zinc acetate dihydrate. METHODS: Sixty-three preterm infants were included in the present study. Serum zinc and copper concentrations, doses, and other clinical characteristics were retrieved from electronic medical records. RESULTS: The medians and interquartile ranges of the dosage and duration of zinc acetate dihydrate were 2.1 (1.8-2.5) mg/kg/day and 12.0 (10.0-13.0) days, respectively. Its administration increased serum zinc concentrations in 39 patients (61.9%) and to more than 70 µg/dL in 16 patients (25.4%). The group with a serum zinc concentration of 70 µg/dL or higher after administration had a significantly higher zinc dose of 2.5 mg/kg/day than the group with a serum zinc concentration of less than 70 µg/dL. Serum copper concentrations did not decrease in 44 patients (69.8%). In the group with a decreased serum copper concentration, postmenstrual age and body weight were significantly lower, while serum zinc concentrations were significantly higher at the start of administration. CONCLUSION: The present results showed that when zinc acetate dihydrate was administered to preterm infants with hypozincemia, it was possible to increase serum zinc concentrations without decreasing serum copper concentrations in many cases. However, caution may be required when administering zinc to preterm infants with a lower postmenstrual age or milder hypozincemia because serum copper concentrations may decrease.

[Role of UGT1A1*28 and UGT1A1*6 for irinotecan-induced adverse drug reaction].

Irinotecan is widely used in the treatment of colorectal, gastric, and lung cancers. However, adverse drug reactions such as severe diarrhea and neutropenia limit the dose of this drug. Irinotecan is metabolized by carboxylesterase to form an active metabolite, 7-ethyl-10-hydroxycamptothecin(SN-38), which in turn is subsequently conjugated by UGT-glucuronosyltransferase 1A1(UGT1A1)to yield an inactive form, SN-38 glucuronide(SN-38 G). The UGT1A1 gene polymorphisms contribute to the individual variation in adverse events among patients administered irinotecan. However, the distribution of polymorphisms shows large interethnic differences. The distribution of UGT1A1*28 greatly differs between Caucasians and Japanese; the frequency of UGT1A1*28 is high in Caucasians, whereas it is low in Asians including Japanese. Recently, it has been demonstrated that genetic variants of UGT1A1*6 in addition to UGT1A1*28 are associated with the occurrence of adverse events in irinotecan chemotherapy in Asians. This review summarizes recent studies to outline the role of UGT1A1*28 and UGT1A1*6 for irinotecan-induced adverse drug reaction in Japanese cancer patients.

Prediction of Apparent Oral Clearance of Small-Molecule Inhibitors in Pediatric Patients.

The purpose of this study was to build regression models for the prediction of apparent oral clearance (CL/F) for small-molecule inhibitors in the pediatric population using data obtained from adults. Two approaches were taken; a simple allometric regression model which considers no interdrug or interindividual variability and an allometric regression model with mixed-effects modeling where some variability parameters are included in the model. Average CL/F values were obtained for 15 drugs at various dosages from 31 literatures (a total of 139 data sets) conducted in adults and for 15 drugs from 26 literatures (62 data sets) conducted in children. Data were randomly separated into the "modeling" or "validation" data set, and the 2 allometric regression models were applied to the modeling data set. The predictive ability of the models was examined by comparing the observed and model-predicted CL/F in children using the validation data set. The percentage root mean square error was 17.2% and 26.3% in the simple allometric regression model and the allometric regression model with mixed-effects modeling, respectively. The predictive ability of the 2 models seems acceptable, suggesting that they could be useful for predicting the CL/F of new small-molecule inhibitors and for determining adequate doses in clinical pharmacotherapy for children.

Pharmaceutical stability of colloidal saccharated iron oxide injection in normal saline.

BACKGROUND: Colloidal saccharated iron oxide injection is used for the treatment of iron deficiency anemia in patients with a poor oral intake. Because of the poor stability of the colloid particle, there have been concerns regarding its compatibility with various injections in clinical practice. To assess the stability of colloidal saccharated iron oxide in normal saline as a diluent, pharmaceutical stability analyses were conducted using various concentrations of glucose and sodium chloride (NaCl). METHODS: Colloidal saccharated iron oxide injection was diluted in three different diluents (5% glucose solution, normal saline, and 10% NaCl solution), and its appearance, colloid particle diameter, and pH were assessed. Free iron ions, which cause adverse effects, such as nausea and vomiting, were separated from the colloid particle using a dialysis membrane for 24 h, and their concentration was determined. RESULTS: No difference in the appearance, colloid diameter, and free iron ion fraction was observed after dilution in 5% glucose solution and normal saline. Conversely, an increased colloid aggregation and iron ion release were observed after dilution in 10% NaCl solution. Although iron colloid is unstable in acidic conditions (pH 4.0-6.0), normal diluents such as 5% glucose and normal saline did not cause colloid destabilization by pH change (pH > 8.0). CONCLUSION: Normal saline may be used as a diluent of colloidal saccharated iron oxide injection as well as glucose solution, which is recommended by the pharmaceutical company. Therefore, normal saline can be used as a diluent of colloidal saccharated iron oxide injection in patients with an underlying disease, such as diabetes mellitus, who are difficult to use glucose solution as a diluent.

A phase I/II pharmacokinetics/pharmacodynamics study of irinotecan combined with S-1 for recurrent/metastatic breast cancer in patients with selected UGT1A1 genotypes (the JBCRG-M01 study).

S-1 and irinotecan combination is attractive for breast cancer refractory to anthracyclines and taxanes. Patients with advanced human epidermal growth factor receptor 2 (HER2)-negative breast cancer previously treated with anthracyclines and taxanes were eligible. Patients with brain metastases and homozygous for UGT1A1 *6 or *28 or compound heterozygous (*6/*28) were excluded. A dose-escalation design was chosen for the phase I portion (level 1: irinotecan 80 mg/m2  days 1-8 and S-1 80 mg/m2  days 1-14 every 3 weeks; level 2: irinotecan 100 mg/m2 and S-1 80 mg/m2 ). Study objectives included determination of the recommended dose for phase II, response rate, progression-free survival (PFS), and safety. Pharmacokinetics and CD34+ circulating endothelial cells (CECs) as pharmacodynamics were also analyzed. Thirty-seven patients were included. One patient at each level developed dose-limiting toxicities; therefore, level 2 was the recommended dose for phase II. Diarrhea was more common in patients possessing a *6 or *28 allele compared with wild-type homozygous patients (46% and 25%). Among 29 patients treated at level 2, PFS was longer for UGT1A1 wt/*6 and wt/*28 patients than for wt/wt patients (12 vs. 8 months, P = 0.06). PFS was significantly longer in patients with a larger-than-median SN-38 area under the curve (AUC) than in those with a smaller AUC (P = 0.039). There was an association between clinical benefit and reduction in baseline CD34+ CECs by S-1 (P = 0.047). The combination of irinotecan and S-1 is effective and warrants further investigation.

UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients.

BACKGROUND: Gene polymorphisms of the UDP-glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) contribute to individual variations in adverse events among patients administered irinotecan, and the distribution of the polymorphisms shows large interethnic differences. Variation in the solute carrier organic anion-transporter family, member 1B1 (SLCO1B1) gene also has a significant effect on the disposition of irinotecan in Asian cancer patients. In the present study, we evaluated the association of genetic polymorphisms of UGT1A1 and SLCO1B1 with irinotecanrelated neutropenia in Japanese cancer patients. METHODS: One hundred and thirty-five consecutive patients treated with irinotecan were enrolled. Genotypes of UGT1A1 (*60, *28, *6, and *27) and SLCO1B1 (*1b, *5, and haplotype *15) were determined by direct sequencing. Severe neutropenia refers to events observed during the first cycle of irinotecan treatment. RESULTS: Severe neutropenia was observed in 29 patients (22%). Six patients were homozygous and 48 heterozygous for UGT1A1*6. Only 1 patient was homozygous for UGT1A1*28. Homozygosity for UGT1A1*6 was associated with a high risk of severe neutropenia (odds ratio [OR], 7.78; 95% confidence interval [CI], 1.36 to 44.51). No significant association was found between severe neutropenia and other UGT1A1 polymorphisms or SLCO1B1 polymorphisms. CONCLUSION: These findings suggest that the UGT1A1*6 polymorphism is a potential predictor of severe neutropenia caused by irinotecan in Japanese cancer patients.

Surgical resection deteriorates gemcitabine-induced leukopenia in pancreatic cancer.

BACKGROUND: Gemcitabine hydrochloride (GEM) is one of the most effective chemotherapeutic agents for pancreatic cancer; however, factors affecting GEM-induced leukopenia have not been clarified yet. In the present study, we analyzed the relationship between patients backgrounds and GEM-induced leukopenia. METHODS: Thirty-eight patients with pancreatic cancer were analyzed for correlation between the dose of GEM and the blood leukocyte number. Moreover, we compared leukopenia in resected and non-resected patients. RESULTS: The incidence of grade 3 or 4 leukopenia was 25% in the non-resected patients, whereas equivalent leukopenia was observed in 57% of the resected patients ( P = 0.048 by the chi(2) test). The relative decrease in blood leukocytes induced by GEM administration was more severe in resected patients (41.3 +/- 9.9%), as compared to non-resected patients (52.6 +/- 16.0%; P = 0.023 by t-test). CONCLUSION: In the present study, we found that the administration of GEM to patients after surgical resection caused more severe leukopenia, as compared to findings in non-resected patients. These data suggested that more frequent monitoring of the leukocyte count and prolonged intervals between GEM administrations are necessary for resected patients with pancreatic cancer.Gemcitabine hydrochloride (GEM) is one of the most effective chemotherapeutic agents for pancreatic cancer; however, factors affecting GEM-induced leukopenia have not been clarified yet. In the present study, we analyzed the relationship between patients' backgrounds and GEM-induced leukopenia.