Lymphangioleiomyoma of the Uterus and Pelvic Lymph Nodes: A Report of 3 Cases, Including the Potentially Earliest Manifestation of Extrapulmonary Lymphangioleiomyomatosis.

We present 3 cases of extrapulmonary lymphangioleiomyomatosis (LAM) identified incidentally in the uterine corpus and pelvic nodes resected for other reasons. One patient, a 47-yr-old female with corpus cancer, underwent a total hysterectomy and nodal dissection; the other 2 patients, aged 44 and 49 yr, underwent simple hysterectomy for corpus leiomyomas. None of the patients had evidence of tuberous sclerosis complex or any significant lesions in other organs. An area of spindle cell proliferation, intimately associated with dilated and tortuous lymphatic vessels, was found in the myometrium of all 3 patients, and nodal involvement with spindle cell proliferation was observed in the patient with corpus cancer. The spindle cells had faintly eosinophilic cytoplasm and a bland appearance. They were immunoreactive for α-SMA, gp100 (HMB45), and Melan-A. Tumor cell clusters lined with a single layer of lymphatic endothelium were floating in the lymphatic vessel lumen. These lesions were diagnosed as lymphangioleiomyoma in the uterine corpus and associated lymph nodes. Two of the cases seemed to be the earliest manifestations of extrapulmonary LAM, and the other case represents early-phase metastasis of LAM from the uterus. The present cases support the speculation that the uterus is the primary source of LAM cells.

CYP7A1 expression in hepatocytes is retained with upregulated fibroblast growth factor 19 in pediatric biliary atresia.

AIM: Bile acid biosynthesis is strictly regulated under physiological conditions. The expression of fibroblast growth factor (FGF) 19 is induced when bile acids bind to the farnesoid X receptor in the intestinal epithelium. Fibroblast growth factor 19 is then transported by the portal flow, causing transcriptional inhibition of cytochrome P450, family 7, subfamily A, polypeptide 1 (CYP7A1), a key enzyme in bile acid biosynthesis, through the extracellular signal-regulated kinase (ERK) pathway. However, the regulatory mechanisms of these signaling pathways in hepatocytes under chronic cholestasis remain unclear. We investigated the regulation of these signaling pathways in patients with biliary atresia (BA). METHODS: We analyzed the regulation of molecules in these signaling pathways using liver and serum samples from eight BA children and four non-cholestatic disease controls. RESULTS: CYP7A1 mRNA expression was not inhibited in BA microdissected hepatocyte-enriched tissue (HET) despite high serum bile acid concentrations. The FGF19 protein was synthesized in BA HET, and its serum concentration was elevated. Fibroblast growth factor receptor 4 was phosphorylated in BA livers. However, ERK phosphorylation was significantly reduced. We examined SPRY2 expression to determine how the ERK pathway was inactivated downstream of the FGF receptor; the expression was significantly increased in BA HET. CONCLUSIONS: This is the first study to measure the CYP7A1 mRNA levels in human BA HET. Fibroblast growth factor 19 was increased in BA hepatocytes. By focusing on its regulation in hepatocytes, we showed that the FGF19 pathway did not suppress bile acid synthesis, probably due to an altered mechanism involving upregulated SPRY2 in BA patients.

[Implementation and Evaluation of Genetic Testing Seminars about Lifestyle-related Disease Prevention in Pharmacy Insurance-The Need for Cooperation between the Pharmacy and the University in Genetic Testing].

A seminar titled "Implementation and evaluation of genetic testing of lifestyle-related disease genes" was held for pharmacists, medical clerks, and clerks of pharmacy insurance, with the aim of holding seminars led by pharmacists for the general public (including patients) in the future. The subject of the seminar was single nucleotide polymorphisms in obesity-related genes and alcohol metabolism-related genes. The purpose of the seminar was to contribute to the prevention of lifestyle-related diseases of the general public. We evaluated it by administering a questionnaire to the participants before and after the seminar. After the seminar, 55% of pharmacists answered that they would like to or would strongly like to participate in genetic testing (for lifestyle-related diseases and drug metabolism-related genes) of the general public. However, some participants did not wish to do so. A customer satisfaction (CS) analysis found that this was mainly because they did not want to know the results of genetic testing of others, which they felt should be private. Most (82%) of the pharmacists answered that assistance and advice was "very necessary" or "necessary" in the participation of genetic testing. These findings show that collaboration between pharmacies and universities will be important for future seminars to the general public.

Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells.

Foxp3+ regulatory T (Treg) cells, which suppress immune responses, are highly proliferative in vivo. However, it remains unclear how the active replication of Treg cells is maintained in vivo. Here, we show that branched-chain amino acids (BCAAs), including isoleucine, are required for maintenance of the proliferative state of Treg cells via the amino acid transporter Slc3a2-dependent metabolic reprogramming. Mice fed BCAA-reduced diets showed decreased numbers of Foxp3+ Treg cells with defective in vivo proliferative capacity. Mice lacking Slc3a2 specifically in Foxp3+ Treg cells showed impaired in vivo replication and decreased numbers of Treg cells. Slc3a2-deficient Treg cells showed impaired isoleucine-induced activation of the mTORC1 pathway and an altered metabolic state. Slc3a2 mutant mice did not show an isoleucine-induced increase of Treg cells in vivo and exhibited multi-organ inflammation. Taken together, these findings demonstrate that BCAA controls Treg cell maintenance via Slc3a2-dependent metabolic regulation.

Mesonephric adenocarcinoma of the uterine corpus with intracystic growth completely confined to the myometrium: a case report and literature review.

BACKGROUND: Mesonephric adenocarcinoma (MA) is a rare tumor believed to arise from mesonephric remnants occurring mostly in the uterine cervix and, to a lesser extent, the corpus. Since the first case report of MA in the corpus in 1995, only 16 cases have been reported in the English literature. A recent report suggested that MA originates in Müllerian tissue and exhibits the mesonephric differentiation phenotype. CASE PRESENTATION: An asymptomatic 61-year-old woman was referred to our hospital because of elevated levels of tumor markers. Imaging revealed an intramural lesion of the uterine corpus exhibiting fluorodeoxyglucose uptake. A total hysterectomy and bilateral salpingo-oophorectomy were performed. The tumor was completely confined to the corpus wall and was composed of an intracystic bulky component and an invasive component in the myometrial layer. The tumor exhibited a variety of growth patterns, including a characteristic tubular pattern with dense eosinophilic secretion reminiscent of the thyroid, as well as a variety of morphologies, such as acinar, papillary, and ductal structures. The structures were immunoreactive for CK7, vimentin, CD10, calretinin, PAX8, and GATA3 and almost completely negative for ER/PgR. CA125 and CA19-9 antigen expression was also detected. CONCLUSION: A case of MA with a unique growth pattern of an intracystic mass within the corpus wall is presented. The histogenesis and differential diagnoses are discussed. The histogenesis of MA is not yet clear. We hypothesize two different pathways involved: 1) direct development from the mesonephric remnants and/or 2) mesonephric transformation of Müllerian adenocarcinoma.

[Implementation and Evaluation of Genetic Testing Seminars on Lifestyle-related Disease Prevention for Pharmacy Students].

The field of pharmacotherapy has advanced to use molecular targeted agents, and pharmacists are now encouraged to focus on pharmacogenomics. A seminar titled "Implementation and evaluation of genetic testing of lifestyle-related disease genes" was presented to students at the Faculty of Pharmaceutical Sciences, Hiroshima University, describing the pharmacogenomic role of single nucleotide polymorphisms in obesity-related genes and alcohol metabolism-related genes. The seminar topic was selected first because pharmaceutical students were already familiar with some of the content, and secondly because we believe that pharmacists should be informed about the prevention of lifestyle-related diseases using genetic testing. We evaluated the usefulness of this seminar by administering a questionnaire before and after the seminar to participating students. Several points requiring improvement were identified, although 82% of students stated that the seminar was "very useful" or "useful". We conclude that this educational seminar was useful to students of pharmaceutical sciences.

[Health assessment of local residents who made full use of symptomatology skills and test device].

A strategy named "Japan is back" adopted in June 2013 specifies that pharmacies shall be regarded as community-based places where health-related information is provided, and the public shall be encouraged to use the services of pharmacies and pharmacists who can advise on health and appropriate use of over-the-counter (OTC) drugs, and promote self medication. In Japan there are approximately 55000 pharmacies and 260000 pharmacists, and community residents are recommended to use these resources. As advisors on healthcare in the community, pharmacists are required to make judgments regarding drug use in individuals performing self medication and using OTC drugs in consideration of their symptoms and level of understanding of their health conditions, and recommend that they consult a medical center if necessary. To meet these requirements pharmacists need to have the skills to monitor each individual's lifestyle, behavior, and environment as well as trends in society, and assess their health status. However, education that allows pharmacists to practice such skills remains insufficiently developed. We consider that to be able to detect diseases early among community residents and appropriately support them using pharmacotherapy, it is very important to train pharmacists to do the following at pharmacies: 1) determine individuals who should be treated early using symptomatologic skills; 2) promote public awareness of disease; and 3) perform biochemical examination (blood is collected by fingerprick promptly to obtain biochemical data) in cooperation with the Department of Clinical Pharmacotherapy, Faculty of Pharmaceutical Sciences, Hiroshima University.

The ectoenzyme E-NPP3 negatively regulates ATP-dependent chronic allergic responses by basophils and mast cells.

Crosslinking of the immunoglobulin receptor FcεRI activates basophils and mast cells to induce immediate and chronic allergic inflammation. However, it remains unclear how the chronic allergic inflammation is regulated. Here, we showed that ecto-nucleotide pyrophosphatase-phosphodiesterase 3 (E-NPP3), also known as CD203c, rapidly induced by FcεRI crosslinking, negatively regulated chronic allergic inflammation. Basophil and mast cell numbers increased in Enpp3(-/-) mice with augmented serum ATP concentrations. Enpp3(-/-) mice were highly sensitive to chronic allergic pathologies, which was reduced by ATP blockade. FcεRI crosslinking induced ATP secretion from basophils and mast cells, and ATP activated both cells. ATP clearance was impaired in Enpp3(-/-) cells. Enpp3(-/-)P2rx7(-/-) mice showed decreased responses to FcεRI crosslinking. Thus, ATP released by FcεRI crosslinking stimulates basophils and mast cells for further activation causing allergic inflammation. E-NPP3 decreases ATP concentration and suppresses basophil and mast cell activity.

Gas chromatography-electron ionization-mass spectrometry quantitation of valproic acid and gabapentin, using dried plasma spots, for therapeutic drug monitoring in in-home medical care.

A simple and sensitive gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) method using dried plasma spot testing cards was developed for determination of valproic acid and gabapentin concentrations in human plasma from patients receiving in-home medical care. We have proposed that a simple, easy and dry sampling method is suitable for in-home medical patients for therapeutic drug monitoring. Therefore, in the present study, we used recently developed commercially available easy handling cards: Whatman FTA DMPK-A and Bond Elut DMS. In-home medical care patients can collect plasma using these simple kits. The spots of plasma on the cards were extracted into methanol and then evaporated to dryness. The residues were trimethylsilylated using N-methyl-N-trimethylsilyltrifluoroacetamide. For GC-EI-MS analysis, the calibration curves on both cards were linear from 10 to 200 µg/mL for valproic acid, and from 0.5 to 10 µg/mL for gabapentin. Intra- and interday precisions in plasma were both ≤13.0% (coefficient of variation), and the accuracy was between 87.9 and 112% for both cards within the calibration curves. The limits of quantification were 10 µg/mL for valproic acid and 0.5 µg/mL for gabapentin on both cards. We believe that the present method will be useful for in-home medical care.

Impact of cow's milk allergy on enterocolitis associated with Hirschsprung's disease.

PURPOSE: To investigate the impact of cow's milk allergy (CMA) on infants with Hirschsprung's disease (HD). METHODS: Twenty-four patients, who developed gastrointestinal symptoms before the age of 60 days and underwent surgery for HD in the period between January 2003 and December 2012, were enrolled in this study. They were divided into two groups based on CMA-related findings: stimulation index of lymphocyte stimulation test >300 % and the presence of eosinophilic infiltration in the resected colon. Ten patients were determined specimen as not having CMA (Group A), because they did not satisfy any of the criteria. The remaining 14 were determined as having possible CMA (Group B), because they satisfied either or both findings. Patient background characteristics, pre- and postoperative clinical history, and laboratory data were compared between Groups A and B. RESULTS: Pre- and postoperative enterocolitis did not occur in Group A patients. Postoperative enterocolitis was more frequent in Group B than in Group A (p = 0.04). Other clinical and laboratory data did not show significant difference between the two groups. CONCLUSION: CMA is a possible risk factor for postoperative enterocolitis in patients with HD.

Population pharmacokinetic-pharmacodynamic target attainment analysis of imipenem plasma and urine data in neonates and children.

BACKGROUND: Population pharmacokinetic (PK)-pharmacodynamic target attainment analysis of imipenem was performed to elucidate the PK properties in neonates and children and to rationalize and optimize dosing regimens. METHODS: Population PK models were separately developed in neonates and children by simultaneously fitting plasma and urine data from 60 neonates and 39 children. The newly developed models were then used to estimate the probability of attaining the pharmacodynamic target (40% of the time above the minimum inhibitory concentration) against clinical isolates of common bacteria in pediatric patients. RESULTS: The data were best described by a 1-compartment model in neonates and a 2-compartment model in children, respectively. Renal clearance in children (0.187 L/h/kg) was double that of neonates (0.0783 L/h/kg), whereas the volume of distribution at steady-state was approximately 1.8-fold larger in neonates (0.466 L/kg) than in children (0.260 L/kg). Age was not a statistically significant covariate in the PK of both groups. Infusions (0.5 h) of 15 mg/kg every 8 h (45 mg/kg/day) and 25 mg/kg every 12 h (50 mg/kg/day) were shown to be sufficient against common bacterial isolates in both patient populations. However, 1.5-h infusions of 25 mg/kg every 8 h (75 mg/kg/day) in neonates and 25 mg/kg every 6 h (100 mg/kg/day) in children were required to be effective against Pseudomonas aeruginosa (minimum inhibitory concentration for 90% of the isolates=16 µg/mL). CONCLUSIONS: These results explain the changes in imipenem PK properties during the human growth process and provide guidance for tailoring dosing regimens in each pediatric age group.

Prostatic penetration of meropenem in humans, and dosage considerations for prostatitis based on a site-specific pharmacokinetic/pharmacodynamic evaluation.

The aims of this study were to investigate the penetration of meropenem (MER) into human prostate tissue and to assess MER regimens for prostatitis by performing a site-specific pharmacokinetic/pharmacodynamic evaluation. Patients with prostatic hypertrophy (n=49) prophylactically received a 0.5-h infusion of MER (250 mg or 500 mg) before transurethral resection of the prostate. MER concentrations in plasma (0.5-5h) and prostate tissue (0.5-1.5h) were measured chromatographically. Concentration data were analysed pharmacokinetically with a three-compartment model and were used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T>MIC, % of 24h) in prostate tissue, an indicator for antibacterial effects at the site of action. The prostate tissue/plasma ratio was 16.6% for the maximum drug concentration and 17.7% for the area under the drug concentration-time curve, irrespective of the dose. Against MIC distributions for clinical isolates of Escherichia coli, Klebsiella spp. and Proteus spp., 500 mg once daily achieved a >90% probability of attaining the bacteriostatic target (20% T>MIC) in prostate tissue, and 500 mg twice daily achieved a >90% probability of attaining the bactericidal target (40% T>MIC) in prostate tissue. However, against the Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability of attaining the bacteriostatic or bactericidal targets.

Ecto-nucleoside triphosphate diphosphohydrolase 7 controls Th17 cell responses through regulation of luminal ATP in the small intestine.

Extracellular ATP is released from live cells in controlled conditions, as well as dying cells in inflammatory conditions, and, thereby, regulates T cell responses, including Th17 cell induction. The level of extracellular ATP is closely regulated by ATP hydrolyzing enzymes, such as ecto-nucleoside triphosphate diphosphohydrolases (ENTPDases). ENTPDase1/CD39, which is expressed in immune cells, was shown to regulate immune responses by downregulating the ATP level. In this study, we analyzed the immunomodulatory function of ENTPDase7, which is preferentially expressed in epithelial cells in the small intestine. The targeted deletion of Entpd7 encoding ENTPDase7 in mice resulted in increased ATP levels in the small intestinal lumen. The number of Th17 cells was selectively increased in the small intestinal lamina propria in Entpd7(-/-) mice. Th17 cells were decreased by oral administration of antibiotics or the ATP antagonist in Entpd7(-/-) mice, indicating that commensal microbiota-dependent ATP release mediates the enhanced Th17 cell development in the small intestinal lamina propria of Entpd7(-/-) mice. In accordance with the increased number of small intestinal Th17 cells, Entpd7(-/-) mice were resistant to oral infection with Citrobacter rodentium. Entpd7(-/-) mice suffered from severe experimental autoimmune encephalomyelitis, which was associated with increased numbers of CD4(+) T cells producing both IL-17 and IFN-γ. Taken together, these findings demonstrate that ENTPDase7 controls the luminal ATP level and, thereby, regulates Th17 cell development in the small intestine.

Penetration of meropenem into human pancreatic juice.

This study examined the penetration of meropenem into pancreatic juice in patients who had undergone hepato-biliary-pancreatic surgery. The patients received a 0.5-h infusion of 500 mg meropenem. The observed maximum concentration (mean ± standard deviation, n = 5) was 39.1 ± 11.2 µg/ml at 0.5 h in plasma and 2.12 ± 0.73 µg/ml at 1.10 ± 0.14 h in pancreatic juice. The pancreatic juice/plasma ratio was 0.06 ± 0.02. The area under the drug concentration-time curve was 73.0 ± 37.5 µg•h/ml in plasma and 4.24 ± 2.77 µg•h/ml in pancreatic juice. The pancreatic juice/plasma ratio was 0.06 ± 0.01. The mean drug-exposure times above 0.125 µg/ml and 0.25 µg/ml (the minimum inhibitory concentrations (MIC) for common pathogens) in pancreatic juice were 99.4% and 87.3%, respectively, for 500 mg meropenem 3 times daily. This commonly used regimen for pancreatitis achieved the drug-exposure time target (40% of the time above the MIC) at the action site, despite the low penetrability of meropenem.

Optimisation of imipenem regimens in patients with impaired renal function by pharmacokinetic-pharmacodynamic target attainment analysis of plasma and urinary concentration data.

In this study, a pharmacokinetic-pharmacodynamic (PK-PD) target attainment analysis of imipenem (IPM) in patients with impaired renal function was conducted. IPM (500 mg) was administered via a 0.5-h or 1-h infusion to 27 patients with varying renal function. A population PK model was developed by simultaneously fitting plasma and urinary concentration data. A two-compartment model adequately described IPM pharmacokinetics, and creatinine clearance (CL(Cr)) was identified as the most significant covariate. A PK-PD simulation predicted the probabilities of attaining the target in plasma [40% of the time above the minimum inhibitory concentration (MIC)] and defined the PK-PD breakpoints (the highest MICs at which the probabilities were ≥90%). In a patient with a CL(Cr) of 90 mL/min, prolongation of infusion time (from 0.5 h to 1.5 h) increased the PK-PD breakpoint from 1 µg/mL to 2 µg/mL with a 500 mg dose every 8h (q8h) and from 2 µg/mL to 4 µg/mL with a 500 mg dose every 6h (q6h). Meanwhile, in a patient with a CL(Cr) of 20 mL/min, the PK-PD breakpoints for both 0.5-h and 1.5-h infusions were 1 µg/mL with a 250 mg dose every 12h (q12h), 2 µg/mL with a 250 mg dose q8h and a 500 mg dose q12h, and 4 µg/mL with a 250 mg dose q6h. These results indicate that a shorter dosing interval is beneficial in patients with impaired renal function as it results in greater PK-PD breakpoints and a reduction in excessive maximum plasma concentrations. These results help to optimise IPM regimens, particularly in patients with impaired renal function.

Humoral immunity is involved in the development of pericentral fibrosis after pediatric live donor liver transplantation.

Although LT can be successful for treating end-stage liver disease in children, some patients develop fibrosis around the central vein area (PCF). This raises the possibility that PCF could lead to later cirrhosis and graft failure. Here, we report a retrospective immunohistochemical study of 28 patients who received a live donor liver transplant. We assessed the incidence and etiology of PCF using CD3, CD20, HLA-DR, and C4d-specific antibodies. Histological evidence of PCF was found in 13 cases (46.4%), of which 11 (84.6%) had experienced ACR and/or CP events post-transplant. Immunohistochemical evaluation revealed significantly stronger staining with these antibodies in the central vein area in PCF, especially for CD20 and C4d. This implies humoral immunopathology and suggests involvement of humoral immunity in the development of PCF. These results further imply that suppression of cellular immunity alone is insufficient to prevent PCF. We therefore suggest that suppression of both humoral and cellular immunity in combination would be required for prevention of PCF.

Determination of doripenem penetration into human prostate tissue and assessment of dosing regimens for prostatitis based on site-specific pharmacokinetic-pharmacodynamic evaluation.

Prostatic hypertrophy patients prophylactically received a 0.5-hour infusion of doripenem (250 or 500 mg) before transurethral resection of the prostate. Doripenem concentrations in plasma and prostate tissue were measured chromatographically, and analysed pharmacokinetically using a three-compartment model. The approved doripenem regimens were assessed based on the time above the minimum inhibitory concentration for bacteria (T>MIC, % of 24 hours), an indicator for antibacterial effects, at the prostate. The prostate tissue/plasma ratios were 17.3% for the maximum drug concentration and 18.7% for the area under the drug concentration-time curve, and they were irrespective of the dose. Against Escherichia coli and Klebsiella species isolates, 500 mg once daily achieved a >90% probability of attaining the bacteriostatic target (20% T>MIC) in prostate tissue, and 500 mg twice daily achieved a >90% probability of attaining the bactericidal target (40% T>MIC) in prostate tissue.

Development and validation of a GC-EI-MS method with reduced adsorption loss for the quantification of olanzapine in human plasma.

A simple and sensitive GC-EI-MS method using solvent extraction and evaporation was developed for the determination of olanzapine concentrations in plasma samples. Because olanzapine and promazine, which was used as the internal standard (IS), are nitrogenous bases, they can adsorb to the weakly acidic silanol groups on the surfaces of glass centrifuge tubes during solvent extraction and evaporation. Silylation of the glass tubes, addition of triethylamine (TEA), and use of a sample solution with a basic pH could prevent adsorption loss. The extraction method involved mixing plasma (500 µL) in a silylated glass tube with a promazine solution (2 µg/mL, 25 µL) in methanol containing 1% TEA. After addition of aqueous sodium carbonate (0.5 mol/L, pH 11.1, 1 mL) and extraction into 3 mL of dichloromethane/n-hexane (1:1, v/v) containing 1% TEA, the organic phase was evaporated to dryness in a silylated glass tube. The residue was dissolved in ethyl acetate containing 1% TEA (50 µL). For GC-EI-MS analysis, the calibration curves of olanzapine in human plasma were linear from 0.5 to 100 ng/mL. Intra- and interday precisions in plasma were both less than 7.36% (coefficient of variation), and the accuracy was between 94.6 and 110% for solutions with concentrations greater than 0.5 ng/mL. The limit of quantification was 0.5 ng/mL in plasma. The assay was applied to therapeutic drug monitoring in samples from three schizophrenic patients.

Importance of evaluating for cow's milk allergy in pediatric surgical patients with functional bowel symptoms.

BACKGROUND: Cow's milk allergy (CMA) can cause functional bowel symptoms. This can lead to confusion and difficulty in managing pediatric surgical patients who also have CMA. We examined CMA's effect on the management of pediatric surgical patients in our institute. METHODS: With institutional review board approval, 14 pediatric surgical patients with CMA were reviewed. Cow's milk allergy was diagnosed according to clinical findings and stimulation index (normal range <300%) of the lymphocyte stimulation test. RESULTS: The main symptoms were abdominal distension (n = 10), vomiting (n = 6), constipation (n = 2), and apnea (n = 1). Stimulation index median value was 731% (range, 341%-2132%). Patients were divided into 3 groups. In group 1 (n = 8), persistent postoperative bowel symptoms were initially considered related to surgical diseases. Following CMA diagnosis, CM elimination therapy improved symptoms. In group 2 (n = 4), CMA was diagnosed concurrently with surgical disease, and elimination therapy was continued postoperatively. In group 3 (n = 2), the pathogenesis of bowel symptoms was initially attributed to CMA and later diagnosed as Hirschsprung's disease. CONCLUSIONS: A high index of suspicion regarding the possibility of concurrent CMA may be necessary to manage bowel symptoms in pediatric surgical patients.

Clinical pharmacokinetics of meropenem and biapenem in bile and dosing considerations for biliary tract infections based on site-specific pharmacodynamic target attainment.

The present study investigated the pharmacokinetics of meropenem and biapenem in bile and estimated their pharmacodynamic target attainment at the site. Meropenem (0.5 g) or biapenem (0.3 g) was administered to surgery patients (n = 8 for each drug). Venous blood samples and hepatobiliary tract bile samples were obtained at the end of infusion (0.5 h) and for up to 5 h thereafter. Drug concentrations in plasma and bile were analyzed pharmacokinetically and used for a Monte Carlo simulation to predict the probability of attaining the pharmacodynamic target (40% of the time above the MIC). Both drugs penetrated similarly into bile, with mean bile/plasma ratios of 0.24 to 0.25 (maximum drug concentration) and 0.30 to 0.38 (area under the drug concentration-time curve). The usual regimens of meropenem (0.5 g every 8 h [q8h]) and biapenem (0.3 g q8h) (0.5-h infusions) achieved similar target attainment probabilities in bile (≥ 90%) against Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates. However, against Pseudomonas aeruginosa isolates, meropenem at 1 g q8h and biapenem at 0.6 g q8h were required for values of 80.7% and 71.9%, respectively. The biliary pharmacodynamic-based breakpoint (the highest MIC at which the target attainment probability in bile was ≥ 90%) was 1 mg/liter for 0.5 g q8h and 2 mg/liter for 1 g q8h for meropenem and 0.5 mg/liter for 0.3 g q8h and 1 mg/liter for 0.6 g q8h for biapenem. These results help to define the clinical pharmacokinetics of the two carbapenems in bile while also helping to rationalize and optimize the dosing regimens for biliary tract infections based on site-specific pharmacodynamic target attainment.