Clinical Impact of an Antibiotic Time Out Initiative at an Academic Medical Center

Background: Various strategies aimed at limiting inappropriate antimicrobial use including antibiotic time out (ATO) have been proposed to combat the development of antimicrobial resistance, yet there are limited studies that have assessed the impact of ATO on clinical outcomes. Methods: This single-center retrospective study reviewed the effect of a passive ATO strategy by comparing 100 adult patients with an ATO matched by infection type to 100 antibiotic-treated adult patients lacking an ATO note. Results: No difference in clinical outcomes was observed, however, ATO did result in improved optimization of antibiotic selection and duration, and reduction of piperacillin/tazobactam and vancomycin use. Conclusion: Further studies are warranted to evaluate the impact of ATO on clinical outcomes of a larger homogenous population with specified infectious diagnoses and clinical characteristics.     

Contribution of intestinal microfloral metabolism to the total macromolecular covalent binding of 1-nitro-pyrene in the lung and liver of the rat

1-Nitropyrene (NP) is a direct acting mutagen found in diesel exhaust and coal-combustion fly ash. The purpose of this study was to investigate the contribution of gut microfloral metabolism to the macromolecular covalent binding (MCB) of NP and/or its metabolites in lungs and liver of the rat. Normal and antibiotic treated rats were administered [14C]NP and MCB was quantitated at various times in lungs and livers. Abolition of gut microfloral metabolism by antibiotic treatment significantly altered total MCB in lungs. MCB in lungs of antibiotic-treated animals 4 h after oral administration of NP was 0.15 nmol NP equivalents/g and was significantly (P less than 0.05) decreased to less than one-half of control values (0.42 nmol NP equivalents/g). MCB in lungs of antibiotic-treated rats was no different from the controls 1 week after NP administration (0.1 nmol NP equivalents/g). Comparison of livers from control and antibiotic-treated rats demonstrated the same pattern of MCB as lungs but differences were not significant. These results reveal that metabolism by gut microflora may play a role in the activation and covalent binding of NP to macromolecules. However, the alteration of covalent binding observed after antibiotic treatment was a change in the time course of formation and breakdown of covalently bound forms and not an effect on the quantity of bound material remaining at 1 week indicating that gut microfloral metabolism is not an exclusive pathway for bioactivation of NP in the rat.     

硝吡咯菌素菌种选育

目的把一种新的方法应用于提高硝吡咯菌素工业生产菌株的生产能力。方法在硝吡咯假单胞菌中引入氨基糖苷类抗生素抗性突变 ,以提高硝吡咯菌素的生产能力。结果从含 3倍和 1 0倍MIC抗生素的GYM筛选平板上挑取抗性突变株 ,挑选出产抗能力提高 5倍以及 1 0倍以上的突变株 ;引入链霉素抗性突变对提高硝砒咯菌素的生产能力的效果最佳 ;Geniticin和庆大霉素的抗性突变对提高抗生素生产能力的效果较差 ;潮霉素抗性突变对提高抗生素生产能力具有一定的效果。结论引入氨基糖苷类抗生素抗性突变 ,可以有效提高硝吡咯菌的生产能力。     

The effects of ozone on lung, heart, and liver superoxide dismutase and glutathione peroxidase activities in the protein-deficient rat

The effects of protein deficiency or food restriction and ozone exposure on lung, heart and liver superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were studied in weanling and adult rats. Two groups of rats were fed diets containing 4 or 16% protein. A third group was fed the 16% protein diet, but at the level consumed by the rats fed the 4% protein diet. After 3 weeks (weanling) or 5 weeks (adult), one-half of the rats in each group were exposed continuously to 0.64 ppm ozone for 7 days. In adult rat lung, O3 exposure typically stimulated Cu,Zn-SOD and GPx activities in all groups, but in weanling rats only GPx activity was elevated and only in rats fed the 16% protein diet. Liver Cu,Zn-SOD activity was also influenced by diet; in adult rats, liver Mn-SOD and GPx activities were often depressed following O3 exposure. Heart SOD and GPx, however, were not affected by ozone or diet. The pulmonary and hepatic effects due to diet and O3 further illustrate the importance of nutritional status when assessing the health effects of O3 exposure.     

Interaction of baicalin and baicalein with antibiotics in the gastrointestinal tract

To clarify the absorption mechanism of baicalin and to investigate the interaction between baicalin and antibiotics, the pharmacokinetics of baicalin and its aglycone baicalein in normal rats and in antibiotic-treated (with a mixture of neomycin and streptomycin) rats were investigated. A method of liquid chromatography-tandem mass spectrometry with a selected reaction monitoring mode was used to determine the plasma concentrations of baicalin and baicalein. The plasma concentration of total baicalein was determined after treatment of beta-glucuronidase/sulfatase. Unpaired Student's t-test was used for statistical comparison. After oral administration of baicalin, the absolute bioavailability of baicalin, based on the AUC of the baicalin parent form, was 2.2+/-0.2% in normal rats, which decreased to 1.5+/-0.2% in antibiotic-treated rats. Based on the AUC of total baicalein after enzymatic hydrolysis, the absorption of baicalin was 28.0+/-5.7%, which significantly decreased to 7.7+/-1.2% in antibiotic-treated rats. After oral administration of baicalein, the glucuronides/sulfates of baicalein were predominant in plasma. Based on the AUC of total baicalein after enzymatic hydrolysis, the absorption of baicalein was 36.1+/-4.4% in normal rats, which did not differ markedly from that in antibiotic-treated rats (P>0.05). The presence of baicalin isomer in plasma after oral administration of baicalin indicated that baicalin was transformed, at least in part, to baicalein before absorption, then to its conjugated metabolites in rats. Aminoglycosides decreased the absorption of baicalin, but not of baicalein, which indicated that antibiotics decreased the decomposition of baicalin to baicalein by inhibiting intestinal flora, and further influenced the absorption, metabolism and efficacy of baicalin. These interactions should be paid attention to in clinical studies when baicalin is administered in combination with antibiotics.     

孕早期高蛋白膳食对子代大鼠CPT1的影响

目的：探讨孕早期高蛋白质膳食（HPD）对子代肥胖和肉碱酰基转移酶1（CPT1）表达的影响,寻找肥胖防治的靶标和合理的孕期膳食。方法孕早期大鼠分别给予HPD和标准膳食（SD）,其后代分别为高蛋白质组（HP）和对照组（CON）,SD喂养至成年,高脂膳食诱导肥胖,FQ-PCR法检测CPT1 mRNA的水平。结果与对照组相比,HPD大鼠子代的体重持续降低（P〈0.05）,CPT1 mRNA水平持续升高。结论孕早期HPD可通过程序性升高子代CPT1 mRNA的水平,降低肥胖的发生。     

Effects of chronic dietary exposure to environmentally relevant concentrations to 2,3,7,8-tetrachlorodibenzo-p-dioxin on survival,growth, reproduction and biochemical responses of female rainbow trout (Oncorhynchus mykiss)

Adult female rainbow trout were exposed to dietary 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at concentrations of 1.8, 18 and 90 ng TCDD/kg (ww) food for up to 300 day. At the end of the exposure fish were spawned and the reproductive outcomes were assessed. TCDD was accumulated into tissues and eggs in a dose-dependent manner with steady state being achieved after 50-100 day of exposure. Biochemical and hematological parameters were monitored at 50, 100, 150, and 200 day after the beginning of exposure. The survival of adult female trout was reduced in a dose-dependent manner by exposure to TCDD in the diet. Fish fed 1.8 ng TCDD/kg, moist weight of diet, showed significantly reduced survival compared with those fed the control diet. TCDD also affected survival of fry from females fed 1.8 ng TCDD/kg. Observed adverse effects in adult fish were as sensitive as early life-stage endpoints. Liver EROD activity was only moderately increased in all exposure groups after 250+ day of exposure. Low rates of edema and deformities were observed in fry from all treatment groups including controls. This study has demonstrated adverse effects of TCDD to both adults and fry at concentrations comparable to current environmental concentrations. This suggests that direct adult toxicity as well as reproductive endpoints need to be incorporated in the current risk assessment paradigm for these compounds.     

Influence of the intestinal microflora on the elimination of warfarin in the rat

The effect of the intestinal microflora on the half-life and elimination of warfarin in rats was examined. When the intestinal microflora was reduced with neomycin, bacitracin, and tetracycline, or was nonexistent as in germ-free animals, more radioactivity was found in feces and less in the urine after ip administration of 14C-warfarin. The ratio of conjugated to free metabolites in the feces was higher in germ-free rats compared to conventional or ex-germ-free animals. In addition, fecal beta-glucuronidase levels were markedly decreased in antibiotic-treated rats and in germ-free rats when compared to conventional and ex-germ-free rats. In a crossover study, a 30% decrease in warfarin half-life was observed in germ-free and antibiotic-treated animals compared to the same rats in an ex-germ-free state. The antibiotic treatment, however, had effects other than reduction of the microflora. A significant decrease in the volume of distribution of warfarin was noted in antibiotic-treated animals which may invalidate the use of this widely used mixture as a model for the study of intestinal microflora-drug interactions. To confirm enterohepatic recycling of warfarin, bile from donor rats administered 14C-warfarin ip was infused into the upper duodenum of recipient rats. Bile from the recipient rats was shown to contain 0.1-0.9% of the radioactivity administered to the donor rats. At 6-8 hr after injection, serum of the recipient rats contained 2-10% of the radioactivity present in the serum from donor rats, and contained mainly free warfarin. These data are consistent with an important role for the intestinal microflora in facilitating enterohepatic recycling of warfarin in the rat.     

A direct HPLC method to estimate streptomycin and its putative ototoxic derivative, streptidine, in blood serum: application to streptomycin-treated humans

Streptomycin is an aminoglycoside antibiotic with a well-known antituberculosis activity; it is commonly used in clinical practice because it is effective and cheap. However, streptomycin has severe ototoxic effects. The delayed and gradual onset may suggest that a metabolic derivative of the antibiotic could be a potential contributor to ototoxicity. As in a rat experimental model this compound was found to be streptidine, we investigated whether this ototoxic metabolite was also present in the blood of streptomycin-treated patients. To this end, we implemented and optimized a direct reverse-phase HPLC technique to identify and estimate streptomycin and streptidine in serum of streptomycin-treated patients. All criteria for validation of the method were implemented in standard curves in serum of healthy non-treated volunteers by addition of increasing concentration of both compounds and their determination in a trichloroacetic acid deproteinized extract. We found that recovery of streptomycin or streptidine was > or =91.5%. Linearity was r(2)> or =0.99. The intraday and interday precisions were < or =9.7 and < or =10.6%, respectively. The relative intraday and interday error ranged from -9.0 to 8.3% for both compounds in human serum. Studies in patients included five male individuals treated from 35 to 90 days with 1g/day of streptomycin, presenting inner ear malfunction from mild to severe, in whose serum streptidine was always present, and could be successfully separated from streptomycin. Therefore, the validated method used can be a valuable tool to measure and follow these compounds in serum of streptomycin-treated patients.     

Excretion and retention of low or moderate levels of aluminium by human subjects

During a 40-day balance study, eight adult males were fed two levels of aluminium: 5 mg/day for 20 days (control diet) and 125 mg/day for 20 days (test diet). Every subject excreted more than 96% and more than 74% of his aluminium intake in his faeces when fed the test and control diets, respectively. Subjects excreted two- to five-fold more aluminium in their urine and had significantly higher levels of aluminium in their sera when fed the test diet rather than the control diet. No retention of aluminium was detected when faecal and urinary losses of aluminium were compared with intakes.     

Metabolic disorders and oxidative stress programming in offspring of rats fed a high-fat diet during lactation: effects of a vinifera grape skin (ACH09) extract

This study examined the effect of Vitis vinifera grape skin ACH09 extract (ACH09) on metabolic disorders and oxidative stress in adult offspring of rats fed a high-fat diet (HF) during lactation. Four groups of female rats were fed: control diet (7% fat); ACH09 (7% fat + 200 mg·kg·d ACH09 orally); HF (24% fat); HF+ ACH09 (24% fat + 200 mg·kg·d ACH09 orally) during lactation. From weaning onward, all female offspring were fed a control diet and killed when they were 90 or 180 days old. Systolic blood pressure was increased in adult offspring of HF-fed dams, and ACH09 prevented hypertension. Increased adiposity, plasma triglyceride, glucose levels, and insulin resistance were observed in offspring from both ages, and these changes were reversed by ACH09. The plasma oxidative damage assessed by malondialdehyde levels was increased, and nitrite levels decreased in the HF group of both ages, which were reversed by ACH09. In addition, ACH09 restored the decreased plasma and mesenteric artery antioxidant activities of superoxide dismutase, catalase, and glutathione peroxidase in the HF group. In conclusion, ACH09 protected normally fed offspring of HF-fed dams during lactation from phenotypic and metabolic characteristics of metabolic syndrome providing an alternative nutritional resource for the prevention of metabolic syndrome.     

Neurobehavioral effects of dietary soy phytoestrogens

Phytoestrogens, plant-derived nonsteroidal estrogens found in high abundance in most soy food products, have been studied for their potential beneficial effects against hormone-dependent cancers and age-related diseases. However, little is known about the influence of phytoestrogens on the brain or behavior. This brief review describes mainly our own studies in rodents that have examined the influence of dietary soy isoflavones on certain aspects of brain structure, learning, memory and anxiety along with the brain androgen-metabolizing enzyme, aromatase. These studies used a commercially available diet rich in phytoestrogens (Phyto-rich) vs. a custom diet relatively free of phytoestrogens (Phyto-free). The phytoestrogen content of each diet was determined by high-performance liquid chromatography analysis, circulating plasma phytoestrogen levels were quantified by gas chromatography mass spectroscopy and concentrations of phytoestrogens in specific brain regions were measured by time-resolved fluoroimmunoassay (TR-FIA). Our studies showed that brain aromatase levels were not significantly altered by phytoestrogen diet treatments in perinatal, maternal or adult rats. However, volumes of the sexually dimorphic nucleus of the preoptic area (SDN-POA) were significantly affected by the Phyto-free diet treatment in male rats during adulthood, where SDN-POA volumes were smaller compared to Phyto-rich male values. Additionally, the Phyto-rich diet fed to adult male and female rats produced anxiolytic effects as assessed in the elevated plus maze vs. Phyto-free fed animals. Finally, when learning and memory parameters were examined in a radial arm maze testing visual-spatial memory (VSM), the diet treatments significantly changed the typical sexually dimorphic pattern of VSM. Specifically, adult Phyto-rich fed females outperformed Phyto-free fed females, while in males on the same diets, the opposite pattern of maze performance was observed. When female vs. male performance was compared, Phyto-rich females executed the VSM task in a manner similar to that of Phyto-free fed males, while Phyto-free fed female's VSM was comparable to Phyto-rich males. These results indicate that consumption of dietary phytoestrogens resulting in very high plasma isoflavone levels (in many cases over a relatively short interval of consumption in adulthood) can significantly alter sexually dimorphic brain regions, anxiety, learning and memory. The findings of these studies identify the biological actions of phytoestrogens, specifically isoflavones and their metabolites, found in animal soy-containing diets on brain and behavior and implicate the importance of phytoestrogens given the recognized significance of estrogens in brain and neural disorders, such as Alzheimer's disease, especially in women.     

Mutational biosynthesis of a new antibiotic, streptomutin A, by an idiotroph of Streptomyces griseus.

Microorganisms producing antibiotics have been genetically converted by earlier workers to mutants which cannot produce antibiotic without supplementation with a moiety of the antibiotic. These antibiotics include neomycin, kanamycin, paromomycin, butirosin, sisomicin, ribostamycin and novobiocin. Success has not been reported for organisms producing guanidinocyclitol antibiotics such as streptomycin. We mutagenized conidia of the streptomycin-producing Streptomyces griseus strain 7-455F3 with nitrosoguanidine at pH 7.0. Non-producers of streptomycin were visually selected by the agar-plug technique using Bacillus subtilis. We successfully isolated mutant MIT-A5 which produces no streptomycin unless streptidine is added to the agar medium. The streptidine-dependent phenotype was confirmed in submerged culture in flasks. Attempts to produce new antibiotics by feeding aminocyclitols to mutant MIT-A5 failed. However a new antibiotic (streptomutin A) was produced by supplementation with the guanidinocyclitol, 2-deoxystreptidine. We propose the term "mutational biosynthesis" for the production of new metabolites by the use of mutants blocked in the biosynthetic pathway to the secondary metabolite. We further propose the term "idiotroph" to properly describe such mutants.     

Prenatal nicotine exposure induces poor articular cartilage quality in female adult offspring fed a high-fat diet and the intrauterine programming mechanisms

Prenatal nicotine exposure (PNE) induces skeletal growth retardation and dyslipidemia in offspring displaying intrauterine growth retardation (IUGR). Cholesterol accumulation resulting from cholesterol efflux dysfunction may reduce the quality of articular cartilage through fetal programming. This study evaluated the quality of articular cartilage of female adult offspring fed a high-fat diet and explored the mechanisms using a rat IUGR model established by the administration of 2.0 mg/kg/d of subcutaneous nicotine from gestational days 11–20. The results demonstrated an increased OARSI (Osteoarthritis Research Society International) score and total cholesterol content, decreased serum corticosterone, and increased IGF1 and dyslipidemia with catch-up growth in PNE adult offspring. Cartilage matrix, IGF1 and cholesterol efflux pathway expression were reduced in PNE fetuses and adult offspring. Therefore, PNE induced poor articular cartilage quality in female adult offspring fed a high-fat diet via a dual programming mechanism.     

Vitamin K-reversible hypoprothrombinemia in rats: comparison of hypoprothrombinemic changes in various strains of rats caused by vitamin K deficiency and antibiotic treatment

Hypoprothrombinemic changes were compared in rats fed various vitamin K-deficient diets. Changes such as prolongation of prothrombin time and activated partial thromboplastin time, decrease in plasma levels of prothrombin and clotting factor VII, and increase in plasma descarboxyprothrombin, appeared in rats maintained on vitamin K-deficient diet, but in rats on ordinary diet (vitamin K-sufficient diet). As the development of hypoprothrombinemia was not significantly different among animals fed various vitamin K-deficient diets, the blood coagulation parameters were concluded to be regulated only by the vitamin K level. Following the development of hypoprothrombinemia, hemorrhaging in various organs was detected in vitamin K-deficient rats, with strain differences in the severity of hemorrhage; Fischer and Wistar strains were more sensitive than the Sprague Dawley strain. Administration of a beta-lactam antibiotic, latamoxef (LMOX), to vitamin K-deficient rats led to enhancement of the hypoprothrombinemic conditions, but LMOX-associated changes in plasma enzyme levels were not detected.     

ARTP诱变结合抗性筛选选育西索米星高产菌株

目的 利用等离子体诱变,结合抗生素抗性筛选,获得西索米星高产菌株。方法 首先通过链霉素抗性筛选,获得一株比出发菌株产抗能力高的S4;随后以S4为出发菌株,经等离子体处理40s,借助巴龙霉素抗性筛选,得到双重抗性菌株。最后对突变株进行再次诱变,并结合高浓度链霉素抗性筛选。结果 获得一株高产突变株M. inyoensis SAAP22,比出发菌株效价提高了38.18%,具有稳定的遗传性能。结论 通过等离子体诱变,结合抗生素抗性筛选,可有效提升伊尼奥小单孢菌的西索米星合成能力,所得高产菌株具有潜在应用价值。     

Avoidance behaviour of young black ducks treated with chromium

Pairs of adult black ducks (Anas rubripes) were fed a diet containing 0, 20, or 200 ppm chromium in the form of chromium potassium sulfate. Ducklings from these pairs were fed the same diets as adults and were tested for their avoidance responses to a fright stimulus. Neither level of chromium had a significant effect on avoidance behavior.     

In vivo TNF induction by culture supernatants of antibiotic-treated Escherichia coli 07:K1. Role of antibiotic class and concentration

Antibiotics may cause an excess release of lipopolysaccharide (LPS) from bacteria and thereby promote the production of tumour necrosis factor (TNF). TNF was measured in the serum of Swiss mice challenged with filtered supernatant of Escherichia coli O7:K1 that had been exposed to various antibiotics in vitro. Expressed as a function of a standardized number of cells remaining after 6 h of exposure to gentamicin, ceftazidime, ciprofloxacin or imipenem, TNF leves associated with antibiotic exposure always exceeded those of controls. However, if differences in the remaining number of bacteria were not taken into account, TNF induction by supernatant of control untreated cultures was greater than that elicited by supernatant from any of the antibiotic-treated cultures. With the exception of imipenem, low-dose antibiotic exposure (0.5 x MIC) invariably induced higher TNF levels than did high-dose exposure (10 x MIC). Considerable antibiotic class- and concentration-related differences were noted. LAL equivalent amounts of LPS released by different antibiotics may diverge in their capacity to induce TNF. Our results do not support the notion that the use of rapidly bactericidal and lytic antibiotics should be avoided.     

Changes in brain serotonin and 5-hydroxyindolacetic acid levels induced by 2,4-dichlorophenoxyacetic butyl ester.

Brain concentrations of Serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) were determined in male, mother and virgin female adult rats after exposure to 69 mg/kg body weight/day of 2,4-dichlorophenoxyacetic butyl ester (2,4-Dbe) during 15 or 45 consecutive days. Both 5-HT and 5-HIAA concentrations were increased in the brain. These effects reverted to levels even lower than controls, when the animals were fed an untreated diet after the 2,4-Dbe treatment. High 5-HT and 5-HIAA brain concentrations were also observed in adult rats born from treated mothers (during pregnancy and lactancy) and fed with or without treated diet after weaning. Two different effects on serotoninergic system were detected: a transient effect if 2,4-Dbe was given to adult rats in a short period of time and a permanent effect if the herbicide was supplied during pre- and post birth period (rat brain development). However, in utero exposed but lactationally cross-fostered rat pups were not affected, suggesting that prenatal exposure did not have any influence on the postnatal status of the neurotransmitter(s).     

白藜芦醇对脂肪肝小鼠肝脏病理损伤的作用

目的:观察白藜芦醇对非酒精性脂肪肝(NAFLD)小鼠肝组织病理损伤的防治作用.方法:40只健康雄性小鼠随机分为:正常对照组、模型组和白藜芦醇低、高剂量组(40,80 mg·kg-1 ·d-1 )4组,正常对照组用普通饲料喂养,其余各组给予高脂饲料喂养,并每周皮下注射四氯化碳一次.实验6周后处死全部小鼠,观察小鼠肝组织学...