A 60-year-old woman with a history of symptomatic seizures secondary to a subarachnoid hemorrhage was admitted to hospital because of a generalized seizure. The following day, her electrocardiogram showed negative T waves in II, III, aVF, and V2-6, and the echocardiogram showed an impaired left ventricular ejection fraction with ventricular apical akinesia. Head magnetic resonance imaging showed no acute brain injury, but single photon emission computed tomography (SPECT) showed hyperperfusion which affected the left temporal cortex in particular. Hyperactivity of the temporal lobe might cause autonomic nervous system dysfunction and might be related to takotsubo cardiomyopathy.

BackgroundCombination therapy of linezolid (LZD) and rifampicin (RFP) may be more effective than monotherapy for treating gram-positive bacterial infections, but several studies have suggested that RFP decreases LZD exposures, thereby increasing the risk of therapeutic failure and emergence of LZD-resistant strains. However, the mechanism of the drug-drug interaction between LZD and RFP is unknown.MethodsWe conducted a prospective, open-label, uncontrolled clinical study in Japanese patients receiving LZD and RFP to evaluate the effect of coadministered RFP on the concentration of LZD. In animal study in rats, the influence of coadministered RFP on the pharmacokinetics of LZD administered intravenously or orally was examined. Intestinal permeability was investigated with an Ussing chamber to assess whether coadministered RFP alters the absorption process of LZD in the intestine.ResultsOur clinical study indicated that multiple doses of RFP reduced the dose-normalized trough concentration of LZD at the first assessment day by an average of 65%. In an animal study, we found that multiple doses of RFP significantly decreased the area under the concentration-time curve, the maximum concentration and the bioavailability of orally administered LZD by 48%, 54% and 48%, respectively. In contrast, the pharmacokinetics of intravenously administered LZD was unaffected by the RFP pretreatment. However, investigation of the intestinal permeability of LZD revealed no difference in absorptive or secretory transport of LZD in the upper, middle and lower intestinal tissues between RFP-pretreated and control rats, even though RFP induced gene expression of multidrug resistance protein 1a and multidrug resistance-associated protein 2.ConclusionsTherapeutic drug monitoring may be important for avoiding subtherapeutic levels of LZD in the combination therapy. The drug-drug interaction between LZD and RFP may occur only after oral administration of LZD, but is not due to any change of intestinal permeability of LZD.Trial registrationUMIN, UMIN000004322. Registered 4 October 2010.

Background Ritodrine hydrochloride (RD), a β2-adrenergic agonist, is widely used as a tocolytic medication to suppress premature labor, but can cause neonatal hypoglycemia, a potentially severe side effect. We examined the incidence and risk factors of neonatal hypoglycemia following maternal intravenous administration of RD. Methods This was a retrospective study of neonates, who had birth weight of ≥2000 g and were delivered at 36 weeks gestation or later in Kanazawa University Hospital from August 2013 to July 2016. We defined neonatal hypoglycemia as blood glucose level < 50 mg/dL. Neonates who were delivered without maternal intravenous RD or who were delivered 8 days or more after stopping maternal RD or who received oral RD were defined as the RD non-administration group, while those delivered within 7 days after stopping maternal RD were defined as the RD intravenous administration group. We examined the incidence and risk factors of RD-induced neonatal hypoglycemia by comparing these two groups. Results We enrolled 603 neonates in this study; 504 (83.6%) showed no neonatal hypoglycemia, while 99 (16.4%) exhibited neonatal hypoglycemia. The incidence of neonatal hypoglycemia was significantly higher (61.7%; 58/94) in the RD intravenous administration group than in the RD non-administration group (8.1%; 41/509) ( p < 0.001). Binomial logistic regression analysis in the RD intravenous administration group showed that maternal age over 35 years (AOR: 3.385; 95% CI, 1.082–10.588, p = 0.036) and the interval to delivery from stopping intravenous administration of RD (AOR: 0.974; 95% CI, 0.953–0.996, p = 0.020) were independent factors associated with neonatal hypoglycemia. The cut-off value of the interval to predict the incidence of neonatal hypoglycemia was about 6 h (sensitivity 82.8%, specificity 63.9%). Conclusions The incidence of neonatal hypoglycemia was significantly increased by maternal intravenous administration of RD. We newly identified maternal age (over 35 years) and the interval to delivery from stopping intravenous administration of RD (within 6 h) as independent risk factors for neonatal hypoglycemia following maternal intravenous administration of RD. In cases with these risk factors, careful blood glucose monitoring is recommended for early detection and treatment of neonatal hypoglycemia.

BackgroundContinuous hemodiafiltration (CHDF) is used as renal replacement therapy for critically ill patients with renal failure, and to treat hypercytokinemia. Since CHDF also clears therapeutic agents, drug pharmacokinetics (PK) should be dependent upon CHDF conditions. Although the antibiotic biapenem (BIPM) is used in patients undergoing CHDF, the optimal therapeutic regimen in such patients has not been fully clarified. In this study, we investigated the PK of BIPM in patients with various levels of renal function undergoing CHDF with polysulfone (PS) membrane, and used PK models to identify the optimal administration regimen.MethodsBIPM (300 mg) was administered by infusion in patients undergoing CHDF (n = 7). Blood and filtrate-dialysate were collected for compartment and non-compartment analysis.ResultsThe sieving coefficient of PS membrane was 1.00 ± 0.06 (mean ± S.D., n = 7), and CHDF clearance of BIPM was found to be the sum of the dialysate flow rate (QD) and filtrate flow rate (QF). Non-CHDF clearance showed inter-individual variability (4.82 ± 2.48 L/h), depending on residual renal function and non-renal clearance. Based on the average PK parameters obtained with a compartmental model, maximal kill end point (over 40 % T > MIC4 μg/mL) was achieved with regimens of 300 mg every 6 h, 300 mg every 8 h, and 600 mg every 12 h. Monte Carlo simulation indicated that 300 mg infusion for 1 h every 6 h was optimal, and the probability of target attainment at MIC2 μg/mL was 90.2 %.ConclusionsOur results establish the optimal regimen of BIPM in patients with various levels of renal function undergoing CHDF with a PS membrane.

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